Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClCCl.C(N(CC)CC)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][N:47]([S:61]([CH3:60])(=[O:63])=[O:62])[CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: -15 °C
Yield: 94.4 %

Procedure:
A 1 L 3-neck round-bottomed flask equipped with a thermometer was charged with 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (25.1 g, 37.7 mmol) in dichloromethane (500 mL, 37.7 mmol). The suspension was stirred at −15° C. and treated with dropwise with triethylamine (52.4 mL, 377 mmol). The resulting solution was treated with methanesulfonyl chloride (8.92 mL, 113 mmol) and stirred at 0° C. for 1 h. The resulting mixture was sonicated and the solid was filtered, washed with water and dried in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (26.5 g, 35.6 mmol, 94% yield). m/z (ESI, positive ion) m/z 744 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:26]1[CH:31]=[CH:30][C:29](OC)=[CH:28][CH:27]=1)[CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:25])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7]C)=O)[CH:2]=[CH2:3].C[O-].[Na+].CN(C)[CH:39]=[O:40].Cl>CO>[CH3:12][O:11][C:9]([C:4]1([CH2:1][CH:2]=[CH2:3])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:40][CH3:39])[CH2:14][C:15]2[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:25][C:5]1=[O:7])=[O:10]
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1c(N)cccc1C(F)(F)F)c1ccc(OC)cc1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCC1(C(=O)OC)C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC

Procedure:
α-(2-Propenyl)-[2-(2-amino-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (9.03 g; 19.4 mmole) and a 25% (by weight) sodium methoxide in methanol solution (20.5 ml; 89.5 mmole; d=0.945; 4.6 eq.) in methanol (100 ml) and dry dimethylformamide (100 ml) were refluxed (~95° C. for four hours. 1N Hydrochloric acid was added with stirring, producing a precipitate that was collected by suction-filtration, washed with water (three times) and dried in vacuo giving ~10 g of the title compound as a solid. The "crude" material was used "as is".
Reaction SMILES: [NH2:1][C@H:2]1[C@H:13]2[C:14]3[C:5](=[CH:6][C:7]([O:21]C)=[CH:8][C:9]=3[CH2:10][C@@H:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:4][CH2:3]1.B(Br)(Br)[Br:24]>C(Cl)Cl>[BrH:24].[NH2:1][C@H:2]1[C@H:13]2[C:14]3[C:5](=[CH:6][C:7]([OH:21])=[CH:8][C:9]=3[CH2:10][C@@H:11]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12]2)[CH2:4][CH2:3]1
Reactant: BrB(Br)Br
Reactant: COc1cc2c3c(c1)C[C@@H](c1ccccc1)C[C@H]3[C@H](N)CC2
Solvent: ClCCl
Product: Br
Product: N[C@@H]1CCc2cc(O)cc3c2[C@H]1C[C@H](c1ccccc1)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.34 g (1.2 mmol) of [1R,8S,9aR] 1-amino-5-methoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene, from Step 7, in 9 mL of methylene chloride is treated with 4.4 mL (4.4 mmol) of a 1M solution of boron tribromide in methylene chloride, added dropwise at -78° C. The reaction is warmed to ambient temperature for 1 hour and recooled to -78° C. and the reaction is quenched with 5 mL of methanol. The reaction mixture is allowed to warm to ambient temperature and stirred for 1 hour. The solvent is removed in vacuo and 5 mL of methanol is added and the solution is concentrated to remove methyl borate by azeotropic distillation to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[S:29][CH:30]=1)[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[Cl-].[CH2:38]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:44]=1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:38]([C:40]1[S:41][CH:42]=[C:43](/[CH:45]=[CH:13]\[C:12]2[C:8]([O:7][CH2:6][C:5]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]4[N:27]=[C:28]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[S:29][CH:30]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:9][N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:44]=1)[CH3:39]
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1csc(N2CCCCC2)n1
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3csc(N4CCCCC4)n3)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 17.8 %

Procedure:
A mixture of 3-[(3-methoxy-4-{[2-(piperidin-1-yl)-1,3-thiazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.76 g), potassium carbonate (0.17 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give 1-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-1,3-thiazol-2-yl]piperidine as colorless crystals (0.13 g, yield 18%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 93-94° C.
Reaction SMILES: CC1(C)CO[CH:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[C:20]5[NH:38][C:23](=[C:24]([CH:30]6OCC(C)(C)C[O:31]6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)[O:4]C1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[CH:5]([C:8]1[C:9]2[NH:13][C:12]([C:14]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[C:15]3[N:45]=[C:18]([C:19]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[C:20]4[NH:38][C:23](=[C:24]([CH:30]=[O:31])[C:25]5[CH:26]=[CH:27][C:28]=1[N:29]=5)[CH:22]=[CH:21]4)[CH:17]=[CH:16]3)=[CH:11][CH:10]=2)=[O:4]
Reactant: CC1(C)COC(c2c3nc(c(C4OCC(C)(C)CO4)c4ccc([nH]4)c(-c4ccccc4)c4nc(c(-c5ccccc5)c5ccc2[nH]5)C=C4)C=C3)OC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=Cc1c2nc(c(C=O)c3ccc([nH]3)c(-c3ccccc3)c3nc(c(-c4ccccc4)c4ccc1[nH]4)C=C3)C=C2
Yield: 86.8 %

Procedure:
As described for 5, a solution of 17 (30 mg, 44 μmol) in CH2Cl2 (5.0 mL) was treated with TFA/water (2.0 mL, 1:1) at room temperature for 3 days. The standard workup including chromatography (silica, CHCl3/hexanes) afforded a purple solid (19.8 mg, 88%): IR (neat) 1672, 1548, 1166 cm−1; 1H NMR δ −2.19 (s, 2H), 7.76-7.83 (m, 6H), 8.15-8.17 (m, 4H), 8.66 (s, 2H), 8.93 (d, J=4.8 Hz, 2H), 9.79 (s, 2H), 9.89 (s, 2H), 12.28 (s, 2H); 13C NMR δ 194.8, 141.0, 134.5, 128.7, 127.2, 109.7, 100.1; LD-MS obsd 519.18; FAB-MS obsd 519.1839, calcd 519.1821 (C34H22N4O2); λabs 440, 535, 607, 655 nm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:32][CH2:33][CH2:34][OH:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[F-].[K+].[CH3:38][CH2:39]N(CC)CC>CN(C=O)C.CO>[Cl:22][C:18]1[CH:17]=[C:16]2[NH:15][C:14](=[O:23])[C:13]3([CH:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:11][C:10](=[O:31])[NH:9][CH:8]3[C:6]3[CH:7]=[C:2]([C:38]#[CH:39])[CH:3]=[CH:4][C:5]=3[O:32][CH2:33][CH2:34][OH:35])[C:21]2=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Br)ccc2OCCO)N1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (60 mg, 0.11 mmol) prepared in example 181b in DMF (2 mL), Et3N (0.3 mL), PdCl2(Ph3P)2 (Aldrich, 15 mg) were added and the mixture was purged with nitrogen and sealed. The vessel was heated on a microwave reactor for 25 min. and the mixture was poured into water. The mixture was extracted with EtOAc. The extracts were combined and dried with sodium sulfate and dried to give a brown oil, which was purified by chromatography on an ISCO machine (30-100% EtOAc/Hexanes) to give a foam. 45 mg. The foam was then dissolved in methanol (4 mL) and KF (Aldrich, 53 mg) was added. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was partioned between EtOAc/water. The organic layer was dried and concentrated and the residue was purified by chromatography on ISCO machine (30-100% EtOAc/Hexane) to give an off-white solid. 25 mg.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18](OCC)=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25].Cl.[NH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(OC)c(Br)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 95 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of ethyl 7-bromo-4-hydroxy-6-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.28 g, 0.68 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.17 g, 1.0 mmol) in 5 mL dioxane was treated with DIPEA (0.26 g, 2.0 mmol). The mixture was warmed to 95° C. and stirred for 3 hours, M+1=496/498. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.28 g of the title compound as a white yellow solid. MS m/e=496/498 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[C:6]([OH:15])[CH:5]=1.[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].[CH3:27][C:28]([CH3:30])=O>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([O:15][CH2:17][CH:18]=[CH2:19])[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[C:8]([O:10][CH2:30][CH:28]=[CH2:27])[CH:9]=1
Reactant: COC(=O)c1cc(O)c(NC(C)=O)c(O)c1
Reactant: CC(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(C(=O)OC)cc(OCC=C)c1NC(C)=O
Reaction time: 17 h

Procedure:
A mixture of 11.25 g. of 4-acetamido-3,5-dihydroxy-benzoic acid methyl ester, 12.1 g. of allyl bromide, 15 g. of dry potassium carbonate and 100 ml. of acetone was boiled and stirred on a reflux condenser for 17 hours. The acetone was removed by distillation. The residue was taken up in water/ethyl acetate. Thereafter, the organic phase separated, washed with water, dried and evaporated. Afters recrystallization from ethyl acetate/petroleum ether, there was obtained 4-acetamido-3,5-diallyloxy-benzoic acid methyl ester having a melting point of 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:21]2[C:25]([NH2:26])=[CH:24][N:23]([CH3:27])[N:22]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:26][C:25]3[C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=4)=[N:22][N:23]([CH3:27])[CH:24]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: Cn1cc(N)c(-c2cccc(Cl)c2)n1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cccc(Cl)c2)n1
Reaction time: 1 h

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.166 g, 0.768 mmol) in dichloromethane (8 mL) was added 3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-amine (73.6 mg, 0.354 mmol) and triethylamine (0.20 mL, 1.4 mmol) at room temperature. After 1 hour, the reaction mixture was partitioned between dichloromethane and half-saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated to yield 5-chloro-N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which is carried forward without purification. LCMS (ESI) m+H=387.1.
Reaction SMILES: S(C)C.[CH2:4]([Mg]Br)[CH3:5].[B-](F)(F)(F)[O+](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH:30]=[CH:29][C:28](=[O:31])[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH:30]([CH2:4][CH3:5])[CH2:29][C:28](=[O:31])[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)C1CC(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Agent: C[O+](C)[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)C1CC(=O)CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 88.9 %

Procedure:
CuBr2.SMe2 (19.13 g, 93.1 mmol) was placed into a flame-dried flask along with THF (250 ml). The mixture was cooled to −78° C. and ethylmagnesium bromide (31 ml, 3.0 M in ether, 93.1 mmol) was added slowly. The reaction was stirred for 45 minutes under nitrogen. Boron trifluoride dimethyl etherate was added (11.7 ml, 93,1 mmol) and the mixture stirred for 5 minutes. Ethyl 1-(4-chlorophenylsulfonyl)-4-oxo-1,2,3,4-tetrahydropyridine-2-carboxylate (103; 8.0 g, 23.3 mmol) was added via syringe pump over a 2 hour period while maintaining −78° C. bath temperature. The reaction was stirred for 4 hours and quenched with a 1:1 solution of 2% NH4Cl/NH4OH. An equal amount of EtOAc and water was added and the mixture was filtered to remove solids. The layers were separated and the aqueous layer was extracted with two more portions of EtOAc. The organic layers were combined and dried over Na2SO4 and concentrated to yield a colorless oil (7.74 g). The material was purified by column chromatography using EtOAc/hexanes gradients to yield 5.84 g (67%) of a mixture of cis/trans (4:96) isomers.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH3:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:26]3[CH2:25][CH2:24][N:23]([C@@H:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)[CH3:22])[CH2:28][CH2:27]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: C[C@H](c1ccc(F)cc1)N1CCNCC1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 84 %

Procedure:
A stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (103 mg, 0.5 mmol), (R)-1-[1-(4-fluorophenyl)ethyl]piperazine (125 mg, 0.6 mmol) (prepared as described in J. Med. Chem. 2007, 50, 3528) and DIPEA (97 mg, 0.75 mmol, 129 μl) in DMF (2 mL) was heated at 100° C. for 2 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-(difluoromethyl)-6-[4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine (158 mg, 84%) as a crisp foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH:10]=[CH:11][CH2:12][C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:13]([CH2:12]/[CH:11]=[CH:10]/[C:9](=[O:16])[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[O:15])=[CH:27][CH:26]=1
Reactant: O=C(O)CC=CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)C/C=C/C(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A solution of 4-(3,4-dichlorophenyl)-4-oxo-2-butencarboxylic acid (2.0 g, 8.16 mmol) and oxalyl chloride (0.84 ml, 9.79 mmol) in chloroform (25 ml), was maintained at room temperature under nitrogen atmosphere for 3 hours. The solvent was removed under vacuum and the residue evaporated twice from toluene with the rotary evaporator to remove traces of oxalyl chloride. The thus obtained acid chloride was dissolved in methylene chloride (15 ml) and cooled at -78° C., under inert atmosphere. TEA (1.25 ml, 9.79 mmol), 4-DMAP (0.1 g, 0.816 mmol) and 4-methoxy benzylamine (1.12 g, 8.16 mmol) were added while magnetic stirring was continued at -78° C. for 4 hours. The reaction mixture was allowed to warm at room temperature and then diluted with methylene chloride (100 ml); the organic phase was washed with 1N HCl (3×10 ml), saturated potassium bicarbonate (3×10 ml), brine (3×15 ml), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography, using cyclohexane/ethyl acetate 0÷5 as eluent. The title compound was obtained as a light yellow solid (1.84 g, 62w) (m.p. 169°-170° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[C:3]=1[Cl:10].C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=1[N+:25]([O-:27])=[O:26]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[C:19]=2[N+:25]([O-:27])=[O:26])=[C:4]([Cl:9])[C:3]=1[Cl:10]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: Nc1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-amino-2,3-dichlorophenol (1.00 g, 5.62 mmol) in dry DMF (20 mL) under N2 was added K2CO3 (854 mg, 6.18 mmol) and the mixture kept at RT for 10 min and then treated with a solution of 4-chloro-3-nitropyridin-2-amine (1.024 g, 5.90 mmol) in dry DMF (5.0 mL) in a single portion. The reaction mixture was maintained at RT for 19 hr and was then partitioned between EtOAc (100 mL) and water (100 mL). The aq layer was separated and was extracted with EtOAc (4×70 mL) and the combined organic extracts were dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 0-70%, gradient elution) to afford 4-(4-amino-2,3-dichlorophenoxy)-3-nitropyridin-2-amine as a dark solid (1.28 g, 70%); Rt 1.85 min (Method 2); m/z 315 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[C:10](B(O)O)[CH:11]=1)=[O:5])[CH3:2].Br[C:16]1[CH:17]=[C:18]2[C:24](I)=[N:23][N:22]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]2=[N:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:40]([O:43][CH2:44][CH3:45])(=O)C>O>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:24]([C:10]4[CH:11]=[CH:6][CH:4]=[CH:45][C:44]=4[O:43][CH3:40])=[N:23][N:22]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]3=[N:20][CH:21]=2)[CH:9]=[N:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1cncc(B(O)O)c1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cncc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)c1
Yield: 61 %

Procedure:
A mixture of 3-ethoxycarbonyl-5-pyridylboronic acid (529 mg, 1.91 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (66 mg, 0.09 mmol) and 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (780 mg, 1.80 mmol) acetonitrile (5 mL) and 2 M aqueous solution of sodium carbonate (5 mL) were added and the mixture was irradiated in a Personal Chemistry Optimizer to 90° C. for 30 minutes. The crude reaction mixture was distributed between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-nicotinic acid ethyl ester (552 mg, 61% yield) as a yellow oil. 1H-NMR (500 MHz, d6-DMSO) δ 9.24 (d, 1H), 9.12 (d, 1H), 9.03 (d, 1H), 8.60 (t, 1H), 8.56 (d, 1H), 7.66 (dd, 1H), 7.51 (ddd, 1H), 7.25 (dd, 1H), 7.12 (dt, 1H), 5.88 (s, 2H), 4.40 (q, 2H), 3.87 (s, 3H), 3.71 (t, 2H), 1.37 (t, 3H), 0.87 (t, 2H), −0.073 (t, 9H). MS: m/z 505 [MH+].
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([Br:15])[CH:5]=1)(=O)[CH3:2].C([SiH](CC)CC)C.CO.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.O>[Br:15][C:6]1[CH:5]=[C:4]([CH2:1][CH3:2])[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=1
Reactant: CC(=O)c1cc(Br)cc2c1OCC2(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Br)cc2c1OCC2(C)C
Temperature: 55 °C
Yield: 86.2 %

Procedure:
A solution of 7-acetyl-5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (Intermediate 13, 0.125 g, 0.5 mmol) in 3 mL of trifluoroacetic acid was treated with triethyl silane (0.9 mL, 11.3 mmol) and the resulting clear, colorless solution was heated at 55° C. for 2 h. The reaction mixture was cooled, treated with 6 mL each of methanol and water, neutralized cautiously with saturated sodium bicarbonate solution and extracted with hexanes. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash column chromatography using 2% ethyl acetate in hexane as the eluent afforded the title compound (0.11 g, 93%) as an oil.
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[CH2:10]([C:14]1[CH:30]=[CH:29][C:17]([C:18]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:10]([C:14]1[CH:30]=[CH:29][C:17]([C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([CH:25]3[O:9][CH2:8][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][O:7]3)=[CH:27][CH:28]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CO)CO
Reactant: CCCCc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCc1ccc(C(=O)Oc2ccc(C3OCC(CCCC)CO3)cc2)cc1
Yield: 67.7 %

Procedure:
A mixture of 2-n-butylpropane-1,3-diol (6.6 g, 0.05 m) and p-(4'-n-butylbenzoyloxy)benzaldehyde (14.2 g, 0.05 m), benzene (100 ml) and a catalytic amount of 4-toluenesulfonic acid was azeotropically refluxed until no more water was collected. The solvent was evaporated and the residue was crystallized from ethanol to yield p-(5-n-butyl-1,3-dioxan-2-yl)phenyl p-n-butylbenzoate (13.4 g 67%) CN 79.2°-80.2° C., NL 160° C.