Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15].C1(C)C=CC=CC=1>CN(C=O)C.O.Cl.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])#[N:3]
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCCC2=O
Reaction time: 6 h

Procedure:
0.41 g (4.5 mmol) of copper(I) cyanide is added to a solution of 1.0 g (4.4 mmol) of 5-bromo-1-tetralone [see J. Org. Chem. 49, 4226 (1984)] in 1.3 ml of DMF, and the reaction mixture is stirred at 160° for 6 hours. The reaction mixture is then cooled to 80°, and a solution of 1.6 g of iron(III) chloride hexahydrate in 2.5 ml of water and 0.44 ml of concentrated hydrochloric acid is added. Stirring is continued for 45 minutes, the reaction mixture is cooled and diluted with water, and extraction is carried out with toluene. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated by evaporation. In that manner there is obtained the title compound in the form of yellow-orange crystals, IR (CH2Cl2): 2220, 1690 cm-1 ; 1H-NMR (CDCl3): δ=8.26 (q,1H); 7.81 (q,1H); 7.43 (t,1H); 3.21 (t,2H); 2.72 (t,2H); 2.23 (m,2H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][O:5][CH2:4]1.[CH:10]([O-])=O.[NH4+:13]>[Pd].O.CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:13][CH3:10])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: COC1COCCC1=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CN[C@H]1CCOC[C@H]1OC
Yield: 45.9 %

Procedure:
A slurry of 3-methoxy-tetrahydro-pyran-4-one (0.4 g, 3 mmol-described in WO03/093266(A1)), ammonium formate (1.9 g, 30 mmol), 10% palladium on charcoal (1 g) in water:MeOH (1:5, 6 ml) was stirred overnight after which time it was filtered through Hyflo, the mixture concentrated to remove the MeOH, the residue taken up in Et2O, dried (Na2SO4) and concentrated to afford the title product (0.2 g, 49%) as a yellow oil (contaminated by 10-20% of the trans isomer). 1H NMR (300 MHz, CDCl3) (cis isomer) δ 1.60-1.80 (2H, m), 2.95-3.00 (1H, m), 3.22-3.43 (5H, m). 3.82-3.95 (1H, m), 4.01-4.13 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.C([Li])CCC.COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[OH:7])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(C=O)c1
Reactant: COc1cccc(Br)c1
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: [Li]CCCC
Product: COc1cccc(C(O)c2cccc(OC)c2)c1
Yield: 100.8 %

Procedure:
3-methoxybenzaldehyde (2.20 ml, 18.08 mmol), 1-bromo-3-methoxybenzene (2.52 ml, 19.89 mmol), and n-butyl lithium (7.96 ml, 19.89 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (10% EtOAc in hexane gradient to 25% EtOAc in hexane in about 40 min.) to give bis-(3-methoxy-phenyl)-methanol as a light yellow oil (4.45 g, 100%): 1HNMR (CDCl3) 7.28-7.21 (m, 2H, Ar), 6.96-6.94 (m, 4H, Ar), 6.82-6.78 (m, 2H, Ar), 5.78 (d, J=3 Hz, 1H, CHOH), 3.78 (s, 6H, 2OCH3 groups), 2.25 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)C.ClC1C=CC(S(ON2C3C=C(Cl)C=CC=3N=N2)(=O)=O)=CC=1.CO>C(Cl)(Cl)Cl>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCN(CC)CC
Agent: O=S(=O)(On1nnc2ccc(Cl)cc21)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of benzoic acid (1.22 g) and triethylamine (1.4 ml) in chloroform (15 ml) is added 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1,2,3-benzotriazole (3.44 g) and the mixture is allowed to stand for 1.5 hours. To the mixture are added methanol (1.6 ml) and triethylamine (1.4 ml), whereby exothermic reaction occurrs. After reacting them for 1 hour and 20 minutes, chloroform is distilled off and to the resulting residue are added water and ether. The ether layer is washed with water, an aqueous sodium hydrogen carbonate and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give methyl benzoate (1.26 g).
Reaction SMILES: [Br-].[C:2]([CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:4][CH2:5][CH3:6])=[O:3].CC(C)([O-])C.[Na+].[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([C:44]2[C:48]([CH:49]=O)=[N:47][O:46][N:45]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[F:40]>C1(C)C=CC=CC=1.C1COCC1>[Cl:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([C:44]2[C:48](/[CH:49]=[CH:7]/[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[N:47][O:46][N:45]=2)=[O:43])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=Cc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (carbethoxymethyl)triphenylphosphonium bromide (3.14 g, 7.32 mmol) in toluene (37 mL) was added sodium tert-butoxide (723 mg, 7.52 mmol) at rt under a nitrogen atmosphere. After stirring for 30 min, a solution of N-(3-chloro-4-fluorophenyl)-4-formyl-1,2,5-oxadiazole-3-carboxamide (811 mg, 3.01 mmol) in THF (10 mL) was cannulated into reaction flask. The resulting solution was heated at 80° C. for 3 h, then cooled to rt overnight. The reaction was quenched with a 1 N HCl solution, the aqueous solution was then extracted with ethyl acetate. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with flash chromatography (30% ethyl acetate/hexane) to give the desired product as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.92 (m, 2 H), 7.65 (m, 1 H), 7.26 (m, 1H), 7.01 (m, 1 H), 4.27 (m, 2 H), 1.33 (m, 3 H); LCMS for C14H12ClFN3O4(M+H)+: m/z=340.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1
Reactant: O=Cc1cccn1-c1ncccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Cl)cn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
To a solution of 1.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine in 15 ml of N,N-dimethylformamide was added 0.68 g of N-chlorosuccinimide. The resulting mixture was stirred at 50° C. for 2 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.35 g of 4-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH3:20].[C:21](#[N:25])[CH2:22][C:23]#[N:24].N1CCCCC1>>[NH2:25][C:21]1[O:10][C:11]2[C:19]([CH:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[C:22]=1[C:23]#[N:24])=[CH:18][CH:17]=[C:16]1[N:15]([CH3:20])[CH:14]=[CH:13][C:12]=21
Reactant: O=Cc1cncc(Br)c1
Reactant: Cn1ccc2c(O)cccc21
Reactant: N#CCC#N
Solvent: C1CCNCC1
Product: Cn1ccc2c3c(ccc21)C(c1cncc(Br)c1)C(C#N)=C(N)O3

Procedure:
The title compound was prepared from 5-bromo-pyridine-3-carbaldehyde (44 mg, 0.24 mmol), 4-hydroxy-1-methyl-indole (35 mg, 0.24 mmol), malononitrile (16 mg, 0.24 mmol) and piperidine (0.05 mL), similar to Example 10, and isolated as a solid. 1H NMR (CDCl3): 8.54 (d, J=2.4 Hz, 1H), 8.47 (d, J=1.8 Hz, 1H), 7.60 (m, 1H), 7.08 (d, J=3.0 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.58 (d, J=3.0 Hz, 1H), 4.89 (s, 1H), 4.78 (brs, 2H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][Li].[N:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=3[CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CCOCC.O1CCCC1>[OH:20][C:13]1([CH3:1])[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[CH:10]=[C:9]([N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]1=2
Reactant: O=c1c2ccccc2cc(N2CCCCC2)c2ccccc12
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)c2ccccc2C=C(N2CCCCC2)c2ccccc21
Temperature: 0 °C

Procedure:
A solution of 140 ml. of 1.8 molar methyl lithium in ether and 250 ml. of ether at 5°-10° C. under nitrogen was treated dropwise with a solution of 59 g of 10-(1-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-one in 250 ml of tetrahydrofuran. After a total of 2 hours, the mixture was poured onto ice and allowed to stand until the ice melted. The mixture was extracted well with ether and the extract was dried (Na2SO4), filtered, and concentrated to dryness, the residue being used directly in the next step.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3].[NH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].C(O)C>O>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=Nc1ccc(NCCC(=O)O)c([N+](=O)[O-])c1
Temperature: 55 °C

Procedure:
4-azido-1-fluoro-2-nitro-benzene (90 mg) is mixed with an aqueous solution (0.5 ml) containing 3-aminopropionic acid (53 mg) and Na2CO3 (106 mg). Following addition of 2 ml of ethanol and 0.5 ml of water, the solution is heated for 24 h at 55° C. After removal of the unreacted materials by several ether extractions, the product (3-(N-(4-azido-2-nitrophenyl)-amino)propionic acid) is obtained by ether extraction of the acidified (pH 2.0) aqueous phase.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=1[CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>>[C:5]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:12]=[CH:11][C:10]=1[CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])(=[O:7])[CH3:6]
Reactant: CN(C)CCCCc1ccc(CCCCN(C)C)c(N)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1cc(CCCCN(C)C)ccc1CCCCN(C)C
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To 1 ml of acetic anhydride was added 0.58 g of 2-amino-1,4-bis(4-dimethylaminobutyl)benzene, and the solution was stirred at 50° C. for 2.5 hours. After adding 8 ml of 5% sodium carbonate, the mixture was stirred at a room temperature for 5 hours, alkalized with 10% sodium hydroxide, subjected to salting out and extracted with total 70 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution, dried over potassium carbonate, and evaporated under a reduced pressure to obtain 0.56 g of the title compound as a pale brown crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1C=C([CH:10]=[CH:11][CH:12]=1)N)=[O:4].C(I)C.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](=O)[CH3:26])[CH3:23]>O>[CH3:1][O:2][C:3]([NH:5][C:6]1[CH:26]=[C:25]([CH:10]=[CH:11][CH:12]=1)[N:24]([CH2:22][CH3:23])[CH2:28][CH3:29])=[O:4]
Reactant: COC(=O)Nc1cccc(N)c1
Reactant: CCN(CC)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Product: CCN(CC)c1cccc(NC(=O)OC)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 4.5 g of 3-(methoxycarbonylamino)-aniline, 21.6 g of ethyl iodide, 14.4 g of sodium carbonate, and 90 ml of N,N-diethylacetamide was stirred for 1 hour at 110° C. The reaction mixture obtained was poured into 300 ml of water followed by stirring well and extracted with ethyl acetate. The extract was washed with water, dried by Glauber's salt, and the solvent was distilled off using a rotary evaporator to provide 6.0 g (yield: 100%) of an oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:12])[CH3:11].C.[CH:14](=[O:16])[CH3:15]>C(O)(=O)C>[OH:16][CH:14]([CH3:15])[CH2:11][C:10]([C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: CC=O
Reactant: CC(=O)C1=C(C)C=CCC1(C)C
Agent: C
Solvent: CC(=O)O
Product: CC1=C(C(=O)CC(C)O)C(C)(C)CC=C1
Temperature: 10 °C

Procedure:
Into a 2-liter reaction flask equipped with a mechanical stirrer, cooling bath, 250 ml addition funnel, nitrogen purge, water-cooled condenser, gas bubbler and thermometer, is placed 427 ml (1.3 moles) of a 3-molar solution of methyl magnesium chloride in tetrahydrofuran. 200 Grams (1.22 moles) of 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene are added dropwise from the addition funnel at a rate sufficient to produce methane. Cooling is applied as necessary to maintain the reaction temperature between 30° and 35° C. Following completion of the addition of the 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene, the reaction mass is stirred until no further methane is evolved. The reaction mass is then cooled to a temperature in the range of from 0° C. to 5° C., and 59 grams of acetaldehyde is added dropwise with stirring while maintaining the reaction mass temperature at about 10° C. The reaction is slightly exothermic. 15 Minutes after the completion of the addition of acetaldehyde, acetic acid is added dropwise while maintaining the temperature of the reaction mass at about 10° C. Following the addition of acetic acid, the reaction mass is permitted to reach room temperature. The reaction mass is then washed into a separatory funnel with water to dissolve the salt therein. The resulting organic layer is washed with saturated sodium chloride, saturated sodium bicarbonate, and then saturated sodium chloride. The washed organic layer is then dried over anhydrous magnesium sulfate and concentrated on a rotovap yielding 256 grams of residue.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12]C(OCCOS(C3C=CC(C)=CC=3)(=O)=O)=C[CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:44]([NH:46][CH3:47])[CH3:45].[CH2:48]1[CH2:52][O:51][CH2:50][CH2:49]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:50]([O:51][CH2:52][CH2:48][N:46]([CH2:44][CH3:45])[CH3:47])=[CH:49][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:32])=[O:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Reactant: CCNC
Product: CCN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1ccccc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.363 g, 0.592 mmol) and ethylmethylamine (2.0 mL, 23 mmol) in THF (8 mL) was stirred at 70° C. for 2.5 hours in a sealed tube. After cooling to ambient temperature, the residue was partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 30 minutes gave {2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-ethyl-methyl-amine as a yellow foam/gum (0.241 g, 81.4%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo for 13 hours to yield the hydrochloride as a buff foam (0.242 g). Mass Spectrum (+EI, [M+H]+) m/z 500. 1HNMR (500 MHz, DMSO-d6): δ10.04-10.10 (s, br, 1H), 8.74-8.77 (m, 1H), 8.54-8.56 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.79 (d, 1H, J=9.28 Hz), 7.70-7.74 (m, 1H), 7.55-7.67 (m, 2H), 7.28 (d, 1H, J=2.19 Hz), 7.04-7.20 (m, 6H), 5.70 (s, 2H), 4.35 (s, 2H), 3.33-3.41 (br, 2H), 3.01-3.19 (br, 2H), 2.73 (s, 3H), 1.17-1.21 ppm (m, 3H). Elemental Analysis for C29H29N3O3S.1.00 mol HCl.1.10 mol H2O: Calcd: C, 62.66; H, 5.84; N, 7.56; Found: C, 62.73; H, 6.19; N, 7.17.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:30](=[O:31])[N:11]3[N:12]=[CH:13][C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH3:36][Mg]Br.CO>C1COCC1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:30](=[O:31])[N:11]3[NH:12][CH:13]([CH3:36])[C:14]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:15]([C:16]4[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[C:10]3=[N:9]2)=[CH:5][CH:4]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: C[Mg]Br
Solvent: CO
Solvent: C1CCOC1
Product: CC1Nn2c(nn(Cc3ccc(C(F)(F)F)cc3)c2=O)C(c2ccc(Cl)cc2)=C1c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (250 mg, 0.485 mmol), prepared as described in Example 17, in THF (4 mL) at −20° C. was added methyl magnesium bromide (0.81 mL, 2.43 mmol, 3.0 M in Et2O). The reaction was stirred at −20° C. for 30 min. LC-MS showed that the reaction was complete. To the reaction mixture was added 20 mL of MeOH to quench the reaction. The reaction was allowed to warm to RT and the solvent was evaporated. The residue was diluted with EtOAc (100 mL), washed with H2O (10 mL) and saturated aqueous NaCl (5 mL×2). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using an automated system, eluting with a gradient of (0% to 80% EtOAc for 40 min. and holds at 80% for 10 min.) to give the title compound, 2-(4-(Trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (254 mg), as a beige solid in 98% yield. HPLC retention time: 4.23 min; MS [M+H]+: found 531. 1HNMR (CDCl3, 400 MHz) 67.52 (d, 2H), 7.38 (d, 2H), 7.17-7.11 (m, 4H), 7.05 (dd, 2H), 6.94 (dd, 2H), 4.94 (s, 2H), 4.16 (q, 1H), 1.24 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]#[N:10])[CH:7]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(N)ccn1
Temperature: 145 °C
Yield: 20 %

Procedure:
A mixture of 2-chloro-pyridin-4-ylamine (0.642 g, 5 mmol), Zn(CN)2 (0.323 g, 2.75 mmol) and Pd(PPh3)4 (0.288 g, 0.025 mmol) in 5 mL of DMF was heated at 145° C. for 20 hours. After the reaction mixture cooled to room temperature, it was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide 0.29 g (20%) of the desired product. MS (DCI) m/e 120 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=5.76 Hz, 1H), 6.94 (d, J=2.34 Hz, 1H), 6.68 (dd, J=5.76, 2.37 Hz, 1H), 6.59 (s, 2H).
Reaction SMILES: [ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.F[C:38]1[N:53]=[CH:52][CH:51]=[CH:50][C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH3:49])=[O:41].CN1C(=O)CCC1.Cl>O1CCOCC1>[ClH:1].[ClH:1].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:53]=[CH:52][CH:51]=[CH:50][C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[CH3:49])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 140 °C
Yield: 55.9 %

Procedure:
To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.042 g, 0.17 mmol, Compound C of Example 1) and 2-fluoro-N-o-tolylnicotinamide (0.040 g, 0.17 mmol), in anhydrous 1,4-dioxane (0.22 mL) and anhydrous NMP (0.40 mL), was added HCl (4N in 1,4-dioxane, 0.18 mL, 0.72 mmol). The reaction mixture was heated in a sealed tube at 140° C. for 65 hours before being partitioned between chloroform and 10% LiCl (aq). The aqueous layer was extracted with chloroform and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 34% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to a tan solid that was dissolved in anhydrous THF (1 mL), cooled to 0° C. and treated with HCl (4N in 1,4-dioxane, 0.5 mL, 2.0 mmol). The reaction mixture was stirred for ten minutes, before being lyophilized to afford the title compound (0.025 g, 29%) as a tan solid. 1H NMR (DMSO-d6) δ 12.74 (s, 1H), 10.89 (s, 1H), 10.26 (s, 1H), 8.10-8.50 (m, 4H), 7.10-7.70 (m, 7H), 6.95-7.05 (m, 1H), 6.65-6.75 (m, 1H), 6.45-6.53 (m, 1H), 2.19 (s, 3H);
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]([CH:11]=O)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[C:7]2[C:8]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1csc2cccc(Br)c12
Reactant: NS(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)NCc1csc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Bromobenzothiophene (1.80 g, 8.45 mmol) and dichloromethyl methyl ether (1.46 g, 12.7 mmol) were dissolved in anhydrous DCM (100 mL). Titanium tetrachloride (2.40 g, 12.7 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×150 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 4-bromobenzothiophene-3-carboxaldehyde (0.910 g). The 4-bromobenzothiophene-3-carboxaldehyde (0.910 g, 3.77 mmol) and sulfamide (3.0 g, 31 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.157 g, 4.15 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.