Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:10]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH3:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.C1(C(C2C3C(=CC=CC=3)C=C2)(C)C)C2C(=CC=CC=2)C=C1.[Li].[Li].[Si:50](Cl)([CH3:53])([CH3:52])[CH3:51]>CCOCC.CCCCC>[CH3:51][Si:50]([CH3:53])([CH3:52])[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:2]2)([CH3:11])[CH3:12])[CH:14]=1
Reactant: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C1C=C([Si](C)(C)C)c2ccccc21)C1C=C([Si](C)(C)C)c2ccccc21

Procedure:
5.45 g (20 mmol) of 2,2-bis(indenyl)propane was dissolved in 100 ml of ether. The solution thus obtained was taken to -20° C., and 22 ml of a 2.0 M solution of n-butyl-lithium in pentane was added, thus giving a suspension of dilithium-2,2-(indenyl)propane. 8.77 g (30.85 mmol) of dilithium 2,2-bis(indenyl)propane was dissolved in 100 ml of ether, and 10 ml of Me3SiCl (excess) was added at a temperature of -40° C. The resulting mixture was allowed to return to room temperature. The organic phase was then separated off, the solvent removed and the product dried in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].C1(P(=[CH:40][CH:41]=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:40][CH:41]=[O:42])[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)#[N:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(COc2ccc(C#N)cc2C=O)cc1
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C#N)cc2C=CC=O)cc1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of 3-cyano-6-((4-methoxybenzyl)oxy)benzaldehyde (2.8 g) and (triphenylphosphoranylidene)acetaldehyde (3.5 g) in 40 mL CH2Cl2 was stirred at reflux for 16 hours. The solution was cooled to ambient temperature, concentrated and purified on silica gel column (ethyl acetate/hexane/CH2Cl2, 1:8:3) to give 3-cyano-6-((4-methoxybenzyl)oxy)-1-(2-formylethenyl)benzene (2.8 g) as a yellow solid.
Reaction SMILES: [ClH:1].[CH3:2][C:3]([C:9]([OH:11])=[O:10])([CH2:5][CH2:6][CH2:7][NH2:8])[NH2:4].[Cl:12][CH2:13][CH:14]=[N:15][OH:16]>O>[ClH:12].[ClH:1].[NH2:4][C:3]([CH3:2])([CH2:5][CH2:6][CH2:7][NH:8][C:14](=[N:15][OH:16])[CH3:13])[C:9]([OH:11])=[O:10]
Reactant: CC(N)(CCCN)C(=O)O
Reactant: ON=CCCl
Agent: Cl
Solvent: O
Product: CC(=NO)NCCCC(C)(N)C(=O)O

Procedure:
α-Methyl-D,L-ornithine hydrochloride is protected as a copper complex via reaction with cupric carbonate in water at reflux. This protected amino acid is then reacted with chloroacetaldoxime as in Example 1. The product is eluted from Dowex with 1N ammonium hydroxide. Concentration in vacuo, followed by acidification with hydrochloric acid affords the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH3:15][N:16](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[F:12][C:11]([F:14])([F:13])[CH2:10][O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:16])=[N:3][CH:4]=1
Reactant: FC(F)(F)COCc1ccc(Cl)nc1
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#Cc1ccc(COCC(F)(F)F)cn1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
2-Chloro-5-[(2,2,2-trifluoroethoxy)methyl]pyridine (Intermediate 227, 0.537 g, 2.38 mmol) was dissolved in DMF (6 mL) and zinc cyanide (0.279 g, 2.38 mmol) was added. The mixture was degassed by stirring under a flow of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.275 g, 0.24 mmol) and further DMF (2 mL) were added and the mixture heated to 100 C in a sealed tube for 6 h. The mixture was partitioned between EtOAc (50 mL) and water (50 mL) and the organic layer washed with further water (2×50 mL). The organic layer was dried over sodium sulfate and concentrated to yield an orange oil. This was purified by FCC, eluting with a gradient of 0-30% EtOAc in heptane to afford the title compound as a colourless oil (0.255 g, 50%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.62 (1H, d), 7.79 (1H, dd), 7.66 (1H, d), 4.72 (2H, s) and 3.89 (2H, q).
Reaction SMILES: [CH2:1]([NH:9][NH2:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O=[C:12]([CH2:18][C:19](=O)[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[CH3:20][C:19]1[N:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1
Reactant: NNCCc1ccccc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(CCc2ccccc2)n1

Procedure:
The title compound was prepared from phenethyl hydrazine (3.92 g, 0.029M)(obtained by the method of J. H. Biel U.S. Pat. No. 3,000,903) and ethyl 2,4-dioxovalerate (4.55 g, 0.029M) as described in Example 1, Preparation 1 as a yellow oil (3.84 g, 52%); νmax (CH2Cl2) 1720 cm-1 ;
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[C:36]4[C:31](=[CH:32][N:33]=[C:34](Br)[CH:35]=4)[N:30]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][O:39]4)[N:29]=3)[N:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>CCCCCC.O1CCCC1>[C:6]([CH2:7][C:34]1[CH:35]=[C:36]2[C:28]([C:24]3[N:23]=[C:22]([N:19]4[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[CH2:17][CH2:18]4)[CH:27]=[CH:26][CH:25]=3)=[N:29][N:30]([CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)[C:31]2=[CH:32][N:33]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)CC1
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(CC#N)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
A solution of 0.940 mL of 1.6 M of n-Butyllithium in hexane was added dropwise to a solution of 0.102 mL, (1.95 mmol) of acetonitrile in tetrahydrofuran at −78° C. The mixture was stirred for 30 min and a solution of 272 mg (0.500 mmol) of 4-{6-[5-bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was added. The brown mixture was stirred for 30 min at −50° C. and 2 ml of saturated aqueous NH4Cl was added. The mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The residue was purified via silica gel chromatography using a gradient of ethyl acetate in heptane to afford 44 mg (17%) of tert-Butyl 4-(6-(5-(cyanomethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperazine-1-carboxylate. ESI MS m/z 504.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31](B4OC(C)(C)C(C)(C)O4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:21]4[C:16]5[C:17](=[N:18][C:13]([C:3]6[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=6[Cl:12])=[N:14][CH:15]=5)[NH:19][N:20]=4)[CH:32]=3)[C:27]2=[O:44])[CH2:25][CH2:24]1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CN(C4CC4)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=496.0/498.0
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[C:16](=[O:18])=[O:17].O>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]([OH:18])=[O:17])=[CH:3][C:4]=1[CH3:10])#[N:7]
Reactant: O=C=O
Reactant: Cc1cc(Br)ccc1C#N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in THF (100 ml) at −78° C. under a nitrogen atmosphere was added dropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). The mixture was stirred at −78° C. for 1 h and then poured onto solid carbon dioxide (5 g) in THF (50 ml). The mixture was allowed to warm to room temperature. Water was added (200 ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCl and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.2 g (73%).
Reaction SMILES: Br.[CH2:2]([N:5]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:12]2[C:7](=[C:8]([Cl:24])[C:9]([OH:23])=[C:10]([OH:22])[CH:11]=2)[CH2:6]1)[CH:3]=[CH2:4].[C:25]([Br:28])(=[O:27])[CH3:26]>FC(F)(F)C(O)=O>[BrH:28].[CH2:2]([N:5]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:25](=[O:27])[CH3:26])=[CH:17][CH:16]=2)[C:12]2[C:7](=[C:8]([Cl:24])[C:9]([O:23][C:10](=[O:22])[CH3:9])=[C:10]([O:22][C:18](=[O:21])[CH3:17])[CH:11]=2)[CH2:6]1)[CH:3]=[CH2:4]
Reactant: CC(=O)Br
Reactant: C=CCN1Cc2c(cc(O)c(O)c2Cl)C(c2ccc(O)cc2)C1
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1Cc2c(cc(OC(C)=O)c(OC(C)=O)c2Cl)C(c2ccc(OC(C)=O)cc2)C1
Reaction time: 2 h

Procedure:
A mixture of 1 g of 2-allyl-8-chloro-6,7-dihydroxy-4-(p-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide, 1.3 ml of acetyl bromide and 200 ml of trifluoroacetic acid is stirred at 10° for 2 hours. After evaporation to dryness, the residue is purified, if necessary, by recrystallization to give 2-allyl-8-chloro-6,7-diacetoxy-4-(p-acetoxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide. Similarly tri-isobutyryloxy, -propionyloxy, -isovaleryloxy, -n-butyryloxy and -n-heptanoyloxy ester derivatives are prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:19]=1)[O:10][C:11]([N+:16]([O-:18])=[O:17])([CH3:15])[C:12](Cl)=[O:13].[OH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:28][C:20]1[CH:21]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:23]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:19]=1)[O:10][C:11]([N+:16]([O-:18])=[O:17])([CH3:15])[C:12]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:13]
Reactant: CCOC(=O)CO
Reactant: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)Cl)[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)C(C)(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A solution of 15 g of 5-(2,6-dichloro-4-trifluoromethyl- phenoxy)-2-nitro-α-phenoxypropionyl chloride in 30 ml of toluene was added dropwise to a solution of 3.7 g of ethyl hydroxyacetate and 4 g of triethylamine in 70 ml of toluene cooled to 0° to 5° C. The reaction mixture was stirred at room temperature overnight, diluted with 300 ml of toluene, washed to neutrality, dried, filtered and evaporated. 13.5 g ethoxycarbonylmethyl 5-(2,6-dicloro-4-trifluoromethyl-phenoxy)-2nitro-α- phenoxy-propionate were initially obtained in the form of a yellowish oil which then crystallised. Melting point: 75° to 76° C. The yield of pure substance was calculated to be 70.5% of theory.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH3:10])=[CH:8][C:7]([C:11](Cl)=[O:12])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:11]([C:7]4[CH:8]=[C:9]([CH3:10])[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:6]=4)=[O:12])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1cc(C(=O)Cl)nn1C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)nn1C(C)(C)C
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A dry flask was charged with 1-tert-Butyl-5-methyl-1H-pyrazole-3-carbonyl chloride (0.207 g, 1.032 mmol) and THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 1-tert-Butyl-5-methyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.206 g, 0.490 mmol, 48%).
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+:29].C(O)(C)C>O>[C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][K:29])=[O:25])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: CCCN(CCCC(=O)OC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCN(CCCC(=O)O[K])S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 163.2 %

Procedure:
A round bottom flask fitted with a heating mantle and an overhead stirrer was charged with C4F9SO2N(C3H7)CH2CH2CH2COOCH3 (63.0 g; 0.143 mole), KOH (11.0 g; 0.196 mole; pellets) isopropanol (22 ml.) and deionized water (18 mL). The ensuing mixture was refluxed overnight, cooled to room temperature, yielding a solution of C4F9SO2N(C3H7)CH2CH2CH2COOK (108.6 g; 53.4% solids).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (64 mg, 82%), MS (ISP) m/z=313.4 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[CH3:30][S:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:38][C:37]1[CH:36]=[CH:35][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:41][CH:40]=1)[CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCN3CCOCC3)Cc3ccc(S(C)(=O)=O)cc3)c2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The product from example 1 step (viii) (0.1 g), 4-methylsulphonylbenzyl bromide (0.0673 g) and potassium carbonate (0.0373 g) were combined in DMF (1.5 mL) and stirred at RT for 15 hrs. The reaction mixture was diluted with methanol filtered and purified by RPHPLC to give title compound, 0.039 g
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=O.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:13][CH:12]=1
Reactant: NCc1ccc(N)cc1
Reactant: O=C([O-])c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CNC(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
Pyridine-2-carboxylate (Aldrich; 0.35 g, 2.84 mmol), 4-aminobenzylamine (Aldrich; 0.51 g, 4.26 mmol) and HATU (1.65 g, 4.26 mmol) were dissolved in DMF (7.5 ml). N,N-Diisopropylethylamine (1.5 ml, 8.53 mmol) was added and the mixture stirred at room temperature for 2 h. The mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the residue purified by normal phase chromatography (2% MeOH/DCM) to give a yellow solid (440 mg). which was suspended in DCM/Et2O and filtered to give the title compound as a pale yellow solid (235 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:16](=O)[CH2:17][CH2:18][CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:16]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH2:17][CH2:18][CH3:19]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCNc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 4-(4-fluorophenoxy)aniline (Apollo, 500 mg, 2.46 mmol) and butyraldehyde (240 μL, 2.71 mmol) in DCE (5.0 mL) were added 4 Å molecular sieves. The resulting reaction mixture was stirred at room temperature for 1 h. Next, Na(OAc)3BH (782 mg, 3.69 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Concentration in vacuo afforded a crude residue which was purified by flash column chromatography (10% EtOAc/hexanes) to give the title compound (400 mg, 62%). 1H NMR (CDCl3) δ 7.28-7.21 (m, 2H), 7.20-7.13 (m, 4H), 6.91-6.85 (m, 2H), 3.82 (br s, 1H), 3.39 (t, J=7.0 Hz, 2H), 1.96-1.85 (m, 2H), 1.79-1.67 (m, 2H), 1.26 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 260.1 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][CH2:3]O.[O-]CC.[Na+].Br[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[O:18]1[CH2:3][CH2:2][S:1][CH:10]=[C:11]1[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: OCCS
Reactant: CCOC(=O)CC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1=CSCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A solution of 2-mercaptoethanol (58.5 g.) in anhydrous ethanol (220 cc.) is added, at about 10° C. and over the course of one hour, to a solution of sodium ethoxide in ethanol [prepared by reacting sodium (17.2 g.) with anhydrous ethanol (570 cc.)]. After having heated the reaction mixture to 45°-50° C., ethyl γ-bromoacetoacetate (157 g.) is added over the course of 45 minutes, and then the reaction mixture is stirred for 2 hours at a temperature of about 25° C. After filtration, the solvent is evaporated at about 50° C. under reduced pressure (20 mm.Hg). The residue is dissolved in anhydrous toluene (1,000 cc.) and, after filtration of the resulting solution, toluene-p-sulphonic acid monohydrate (1.5 g.) is added. The reaction mixture is heated under reflux until complete dehydration has taken place (the water formed being removed in a Dean-Stark apparatus) and then toluene (200 cc.) is distilled. After cooling, the toluene solution is filtered and washed twice with a saturated aqueous solution of sodium bicarbonate (200 cc.) and then with water (2 × 200 cc.); it is then dried over sodium sulphate, treated with decolourizing charcoal, filtered and evaporated under reduced pressure (20 mm.Hg). A residue (131.9 g.) is obtained and is chromatographed on alumina (550 g.). Elution is effected using a mixture (2.5 liters) of ethyl acetate and cyclohexane (1-19 by volume) and the eluates are concentrated to dryness under reduced pressure (20 mm.Hg). Ethyl (5,6-dihydro-1,4-oxathiin-2-yl )acetate (75.7 g.) is obtained in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])[CH:6]=[CH:7][CH:8]=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([CH3:18])[CH:11]=1
Reactant: COc1cccc(-c2ccc([N+](=O)[O-])cc2C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cccc(-c2ccc(N)cc2C)c1
Yield: 101.6 %

Procedure:
1-(3-Methoxyphenyl)-2-methyl-4-nitrobenzene(23.4 gm, 96 mmol) was dissolved in a mixture of ethanol and ethyl acetate (3:1, 470 mL) and hydrogenated over 10% palladium on charcoal (2.3 gm) at 3 bar and 20° C. for 2 h. The mixture was filtered through Arbocel filter aid, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give 4-amino-1-(3-methoxyphenyl)-2-methylbenzene (20.8 gm, 100%) as a pinkish-brown oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])=[CH:15][CH:16]=1
Reactant: Clc1ccc(CCCBr)cc1
Reactant: CCc1cnccc1C
Product: CCc1cnccc1CCCCc1ccc(Cl)cc1
Yield: 56.4 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methylpyridine and 3.53 g (15.1 mmol) of 1-bromo-3-(4-chlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.33 g of the desired compound (yield: 56.3%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[I:22]CCI>C1COCC1.ClCCl>[Cl:1][C:2]1[C:3]([I:22])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1
Reactant: ICCI
Reactant: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccccc1-c1nnc2cc(I)c(Cl)nn12
Reaction time: 18 h
Yield: 60.6 %

Procedure:
A solution of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (5.0 g, 15.6 mmol), prepared as in Example 25 Step c), and 1,2-diiodoethane (14 g, 50 mmol) in anhydrous THF (150 ml) was added via cannula to a stirred suspension of tris(dimethylamino)-sulfur (trimethylsilyl)difluoride (5.0 g, 18 mmol) in anhydrous THF (200 ml) at room temperature under nitrogen. After 18 h, the mixture was diluted with dichloromethane (400 ml) and washed sequentially with water (300 ml) and brine (200 ml). The organic layer was dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 3% methanol-dichloromethane, gave crude 6-chloro-3-(2-fluorophenyl)-7-iodo-1,2,4-triazolo[4,3-b]pyridazine (3.54 g) as a dark brown solid. This was subjected to the conditions described in Example 27 Step b) to give 3-(2-fluorophenyl)-7-iodo-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (1.32 g, 19% over two steps) as a yellow solid; 1H NMR (360 MHz, CDCl3) δ3.97 (3H, s), 5.51 (2H, s), 7.28 (1H, dd, J=8 and 8 Hz), 7.37 (1H, dd, J=8 and 8 Hz), 7.56-7.64 (1H, m), 7.86 (1H, ddd, J=7, 7 and 1 Hz), 7.90 (1H, s), 8.68 (1H, s); MS (ES+) m/e 452 [MH]+.