Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[CH:10]=1.[Li+].CC([N-]C(C)C)C.CN([CH:27]=[O:28])C>C1COCC1>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([I:15])[C:10]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: Fc1cccc(I)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1c(F)cccc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
Buthyllithium (1.6 M, 60 ml, 0.113 mol) is added to an ice cooled solution of diisopropyl-amine (17.6 ml, 0.124 mol) in THF (200 ml). The solution is stirred at 0° C. for 30 minutes and is cooled to −78° C. 1-Fluoro-3-iodo-benzene (25 g, 0.113 mol) in THF (20 ml) is slowly added to the preformed LDA mixture. The resulting solution is stirred for another hour after which DMF (9.55 ml, 0.124 mol) is added and stirring is continued for another 30 minutes at −78° C. The reaction is quenched first with acetic acid (20 ml) followed by water (200 ml). The mixture is extracted with ether. The organic layer is washed with a 2N HCl solution, brine, is dried over MgSO4 and evaporated to afford the desired compound (28.3 g).
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[CH2:4]([O:6][C:7](=[O:20])[CH:8](Br)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=O)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[S:2][CH:1]=[N:3][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[O:20])[CH3:5]
Reactant: NC=S
Reactant: CCOC(=O)C(Br)C(=O)c1ccccc1OC
Solvent: CCO
Product: CCOC(=O)c1scnc1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 0° C. solution of thioformamide (prepared according to Eur. J. Med. Chem. 2004, 39, 867-872) (0.70 g, 11.5 mmol) in absolute EtOH (1 ml) was added a solution of 2-bromo-3-(2-methoxyphenyl)-3-oxo-propionic acid ethyl ester (2.4 g, 7.97 mmol) in ethanol abs. (9 ml) in drops. The reaction mixture was stirred at room temperature for 72 hours. After quenching with water and extraction with chloroform, the organics were dried over Na2SO4 and evaporated. Flash chromatography on SiO2 gel (petroleum ether/ethyl acetate, 60/40) gave crude 4-(2-methoxy-phenyl)-thiazole-5-carboxylic acid ethyl ester that was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CO>N1CCCC1>[C:11]([N:18]1[CH2:19][CH2:20][C:21]2([CH2:9][C:8](=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:22][CH2:23]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
The examples listed in Tables 1, 2, and 3 may be prepared according to Schemes 1-57. The synthesis of compounds 1A-1U is outlined in Scheme 1. The 2′-hydroxyacetophenone derivatives 1.1a-1.1m were condensed with 1-Boc-4-piperidone 1.2 in neat pyrrolidine (method 1A) at room temperature or in refluxing methanol in the presence of pyrrolidine (method 1B) to provide N-Boc-spiro[2H-1-benzopyran-2,4′-piperidine]-4(3H)-one derivatives 1.3. Conversion of the ketones 1.3 to the enol triflate derivatives 1.5 was achieved using N-phenylbis(trifluoromethanesulphonimide) 1.4 as triflating reagent. Suzuki type coupling of the enol triflate derivatives 1.5 with either 4-(N,N-diethylaminocarbonyl)phenyl boronic acid 1.6 (commercially available from Combi-Blocks Inc.) or 2-(N,N-diethylaminocarbonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine 1.7 in ethylene glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0) (method 1C) or palladium, 10 wt. % (dry basis) on activated carbon (method 1D), lithium chloride, and an aqueous solution of sodium carbonate afforded compounds 1.8 which were converted to the final products (compounds 1A-1T) under acidic conditions (method 1E: anhydrous HCl, diethyl ether, room temperature or method 1F: neat trifluoroacetic acid, room temperature). Demethylation of compound 1G using boron tribromide provided the corresponding phenolic derivative (compound 1U). The boronate derivative 1.7 was prepared in 4 steps from 2,5-dibromopyridine 1.9. Treatment of 2,5-dibromopyridine with n-butyllithium provided the corresponding lithiated derivative, which reacted with carbon dioxide to provide 5-bromopyridine-2-carboxylic acid 1.10. Treatment of the carboxylic acid derivative 1.10 with oxalyl chloride furnished the acyl chloride 1.11, which reacted with diethylamine 1.12 to provide 5-bromo-2-(N,N-diethylaminocarbonyl)-pyridine 1.13. Conversion of the aryl bromide 1.13 to the corresponding boron derivative 1.7 was achieved using 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane 1.14 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, abbreviated as [Pd(dppf)Cl2.CH2Cl2].
Reaction SMILES: C[O:2][C:3]([C:5]1[S:35][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)[C:7]=2[C:6]=1[CH3:36])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO.O>[C:31]([O:30][C:28]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:22]([O:21][C:15]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[C:6]([CH3:36])=[C:5]([C:3]([OH:4])=[O:2])[S:35][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C

Procedure:
A mixture of 4-[2-((1S,3S)-3-tert-butoxycarbonylamino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg) and lithium hydroxide (133 mg) in THF/MeOH/H2O 1/1/1 (15 ml) was stirred at rt over the weekend. The reaction mixture was acidified with aq. HCl and extracted with DCM. The organic layer was dried, concentrated and the residue was triturated with diisopropyl ether to give the desired compound.
Reaction SMILES: [OH-].[K+].[CH2:3](Cl)/[CH:4]=[CH:5]/[CH2:6]Cl.[C:9]([O:17]CC)(=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>C(Cl)Cl>[CH:4]([CH:5]1[CH2:6][C:10]1([C:9]([OH:17])=[O:16])[C:11]([OH:13])=[O:12])=[CH2:3]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC/C=C/CCl
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Product: C=CC1CC1(C(=O)O)C(=O)O
Yield: 76.8 %

Procedure:
A reaction similar to that described in Example 6 was carried out using solid KOH on a larger scale as follows: To a stirred solution of 550 g (4.4 mol) trans 1,4-dichlorobutene-2, 640 g (4.0 mol) diethyl malonate, 80.7 g tricaprylylmethylammonium chloride in 2.4 liters methylene chloride were added over a one-hour period in small portions 498.7 g (8.0 mol) solid potassium hydroxide flakes (90%). The reaction was then heated to reflux for one hour. Potassium salts were removed by successive additions of water to the reaction mixture and siphoning off the aqueous layer until a total of 1.8 liters of water was added. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and distilled at reduced pressure. The diethyl ester of 2-vinylcyclopropane-1,1-dicarboxylic acid was obtained in 76.8% yield.
Reaction SMILES: N.FC(F)(F)C([N:6]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][OH:26])[C:19]=3[F:27])[CH2:13][CH2:12]2)[O:9][CH2:8][CH2:7]1)=O>CO>[O:9]1[C:10]2([CH2:16][CH2:15][N:14]([CH2:17][C:18]3[C:19]([F:27])=[C:20]([CH2:24][CH2:25][OH:26])[CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)[CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: O=C(N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1)C(F)(F)F
Agent: N
Solvent: CO
Product: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reaction time: 1.5 h

Procedure:
‘880’ Aqueous ammonia solution (5 mL) was added to a solution of 2,2,2-trifluoro-1-(9-(2-fluoro-3-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone (example 67, step e) (1.9 g) in methanol (25 mL). The resulting mixture was stirred for 90 min and the solvent evaporated. The residue was purified by silica gel chromatography eluting with 94.5:5:0.5 to 89:10:1 DCM:methanol:‘880’ ammonia gradient. The fractions containing product were combined and evaporated to give a gum that solidified on standing. The white solid was triturated with isohexane and dried over sodium sulphate to give the subtitled compound as a white solid. Yield 1 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[C:12](=[O:18])[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:4][CH2:3]1.[CH3:23]C([O-])(C)C.[K+].CI.O>C1CCCCC1.C1C=CC=CC=1>[CH3:23][CH:11]1[C:12](=[O:18])[C:13]2[S:14][CH:15]=[CH:16][C:17]=2[C:8](=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]1=2
Reactant: CC(C)(C)[O-]
Reactant: CN1CCC(=C2c3ccccc3CC(=O)c3sccc32)CC1
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CI
Solvent: c1ccccc1
Product: CC1C(=O)c2sccc2C(=C2CCN(C)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
24.5 g of 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one were dissolved in 750 ml of boiling cyclohexane. The mixture was cooled to 50° and whilst this temperature was maintained 10.7 g of potassium tert-butylate were added. The resulting suspension was cooled to 20°, and whilst this temperature was maintained 12.4 g of methyl iodide were slowly added dropwise. The mixture was stirred for a further 1 hour and then treated with 100 ml of water and 100 ml of benzene. The organic phase was separated off and evaporated to yield crude 9-methyl-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-10(9H)-one as an oil which can be used further in crude form (M.Pt. of hydrogen fumarate 213°-215° from ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:71]=[CH:70][C:7]([CH2:8][C:9]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-])=O)=[CH:63][CH:62]=2)([CH2:36][C:37](=[O:59])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([C@H:50]3[CH2:55][CH2:54][C@H:53]([CH2:56][CH2:57][CH3:58])[CH2:52][CH2:51]3)=[CH:46][CH:45]=2)[C:10]([C:13](=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)([CH2:36][C:37](=[O:59])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44]2[CH:45]=[CH:46][C:47]([C@H:50]3[CH2:51][CH2:52][C@H:53]([CH2:56][CH2:57][CH3:58])[CH2:54][CH2:55]3)=[CH:48][CH:49]=2)[C:10]([C:13](=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:27][CH2:28][C@H:29]([CH2:32][CH2:33][CH3:34])[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)([OH:11])[OH:12])=[CH:70][CH:71]=1
Reactant: CCC[C@H]1CC[C@H](c2ccc(OCCCCCC(=O)CC(Cc3ccc([N+](=O)[O-])cc3)(Cc3ccc([N+](=O)[O-])cc3)C(O)(O)C(=O)CCCCCOc3ccc([C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1
Agent: [Zn]
Product: CCC[C@H]1CC[C@H](c2ccc(OCCCCCC(=O)CC(Cc3ccc(N)cc3)(Cc3ccc(N)cc3)C(O)(O)C(=O)CCCCCOc3ccc([C@H]4CC[C@H](CCC)CC4)cc3)cc2)CC1

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 0.975 g (1.00 mmol) 2,2-bis(4-nitrobenzyl)-1,3-di {6-[4-(trans-4-propylcyclohexyl)phenoxy]hexanoyl}propanediol, 1.62 g (6.00 mmol) Ferric chloride hexahydrate and 0.65 g (10.00 mmol) Zinc powder yield 2,2-bis(4-aminobenzyl)-1,3-di {6-[4-(trans-4-propylcyclohexyl)phenoxy]hexanoyl}propanediol.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[C:13]3[C:12]([C:26]3[CH:27]=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:30]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[SiH](C(C)C)(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[C:13]3[C:12]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Sc3ccccc3)cnc21
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(Sc3ccccc3)cnc21
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A mixture of 6 (346 mg, 0.51 mmol), CH2Cl2 (4.4 mL), CF3COOH (410 μL), H2O (41 μL) and i-Pr3SiH (207 μL) were stirred for 0.5 h then added dropwise to a stirred mixture of CH2Cl2/sat. aq. NaHCO3. The layers were separated and the aqueous phase extracted with more CH2Cl2 (3×), dried (MgSO4) and concentrated. The residue was separated by means of silicagel chromatography (SGC) using AcOEt:hexane as eluent in gradient up to 65:35 (v/v) to give 7 as a white solid (160 mg, 72%); 1H NMR (400 MHz, CDCl3+6 drops CD3OD) δ 7.10-7.28 (m, 5H), 7.47 (t, J=7.7 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.75 (s, 2H), 7.78 (s, 1H), 8.01 (d, J=2.1 Hz, 1H), 8.13 (d, J=1.4 Hz, 1H), 8.16 (s, 1H), 8.42 (d, J=2.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][C:13]([OH:15])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[CH:5]=[C:4]2[C:3]=1[CH2:11][CH2:12][C:13]2=[O:15]
Reactant: COc1c(F)ccc(CCC(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1c(F)cc2c(c1Cl)CCC2=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-chloro-4-fluoro-3-methoxyphenyl)propanoic acid (20.74 g, 88 mmol) in benzene (440 mL) was added DMF (0.14 mL, 1.8 mmol) followed by gradual addition of oxalyl chloride (15.4 mL, 177 mmol) during 25 minutes. After 2 hours, the reaction mixture was evaporated under vacuum to give a yellow oil. The oil was dissolved in 100 mL of benzene and evaporated under vacuum. This process was then repeated. The resulting oil was dissolved in dichloromethane (500 mL) and solid aluminum chloride (12.9 g, 96.7 mmol) was added during 5 minutes using a solid addition funnel. After 20 minutes, the reaction mixture was poured onto ca 1000 cc of ice. When most of the ice had melted, the layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed successively with 2N HCl, water and brine. After drying over sodium sulfate, the solution was evaporated under vacuum to give a yellow solid. Flash chromatography through silica gel eluting with EtOAc/hexanes/dichloromethane (10:95:95) gave 4-chloro-6-fluoro-5-methoxyindanone as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24]3[N:25]([C:56]4[N:57]=[CH:58][N:59]=[C:60]([NH2:63])[C:61]=4[N:62]=3)[C@@H:26]3[O:55][C@H:45]([CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@@H:36]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@H:27]3[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1C=CC=C[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].BrCCC[Cl:74]>CO.[Pd]>[Si:29]([O:28][C@@H:27]1[C@H:36]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@@H:45]([CH2:46][O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[O:55][C@H:26]1[N:25]1[C:56]2[N:57]=[CH:58][N:59]=[C:60]([NH2:63])[C:61]=2[N:62]=[C:24]1[NH:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][Cl:74])[CH:10]=2)=[CH:16][CH:17]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCCc3ccc(-c4cccc(OCc5ccccc5)c4)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: ClCCCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCCc3ccc(-c4cccc(OCCCCl)c4)cc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-[2-(3′-benzyloxybiphenyl-4-yl)ethyl-amino]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)adenosine (0.27 g) and 10% palladium-on carbon (56.2 wt % H2O, 0.12 g) in methanol (5 mL) was stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble material was filtered out and the filtrate was concentrated under reduced pressure. To a solution of the residue obtained in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.12 g). Then 1-bromo-3-chloropropane (0.07 mL) was added, and the resulting mixture was stirred at 40° C. for 42 hours. The reaction mixture was partitioned between ethyl acetate (45 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.19 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C>C1COCC1>[C:19]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Oc2cc(Br)ccc2C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2cc(Br)ccc2C(=O)O)cc1
Reaction time: 2.5 h
Yield: 85.7 %

Procedure:
Compound 2f (500 mg, 1.6 mmol) in 10 mL of THF was treated with acetyl chloride (0.15 mL, 2.08 mmol) and triethylamine (0.22 mL, 2.08 mmol). After stirring for 2.5 h the solid was collected. The filtrate was evaporated in vacuo to give 0.48 g of Compound 3f. MS m/z=331 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[N:6]([C:8](=O)[NH:9][N:10]=2)[N:7]=1.P(Br)(Br)([Br:20])=O.N>>[Br:20][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[C:3]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: O=c1[nH]nc2cc(N3CCOCC3)c(Cl)nn12
Reactant: O=P(Br)(Br)Br
Agent: N
Product: Clc1nn2c(Br)nnc2cc1N1CCOCC1
Temperature: 80 °C
Yield: 43.8 %

Procedure:
A mixture of 6-chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolo[4,3-b]pyridazin-3-one (1.1 g, 4.3 mmol) and phosphoryl bromide (25 g) was stirred and heated at 80° C. for 24 hours. Upon cooling the mixture was treated with ice. The aqueous was then basified with aqueous ammonia. The aqueous was then extracted with dichloromethane (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 5% methanol/dichloromethane to give 3-bromo-6-chloro-7-(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine (600 mg). 1H NMR and mass spectrum revealed the product to a mixture of the desired compound and the 6-bromo compound. This mixture was used without further purification. Sodium hydride (60% dispersion in oil, 80 mg, 2.0 mmol) was added in one portion to a stirred solution of the product from above (600 mg) and (1-methyl-1 H-1,2,4-triazol-3-yl)methanol (240 mg, 2.1 mmol; EP-A-421210) in dry DMF at 0° C. under nitrogen. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and then partitioned between ethyl acetate and water. The aqueous layer was further extracted with dichloromethane (×3). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 5 to 8% methanol/dichloromethane to give the title compound (358 mg, 48% for 2 steps). 1H NMR (360 MHz, d6-DMSO) δ3.20-3.22 (4H, m), 3.69-3.71 (4H, m), 3.68 (3H, s), 5.47 (2H, s), 7.41 (1H, s), 8.49 (1H, s); MS (ES+) m/e 395, 397 [MH+].
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:19])[N:5]([C:8]2[CH:13]=[N:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH:9]=2)[C:6]=1[CH3:7].[Cl:20][C:21]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]#[C:28][C:2]2[N:3]=[C:4]([CH3:19])[N:5]([C:8]3[CH:13]=[N:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH:9]=3)[C:6]=2[CH3:7])[CH:24]=[CH:23][N:22]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: COCCn1ncc(-n2c(C)nc(I)c2C)cc1=O
Product: COCCn1ncc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, light brown crystalline solid, MS: m/e=384.2, 386.2 (M+H+), was prepared in accordance with the general method of example 35 from 5-(4-Iodo-2,5-dimethyl-imidazol-1-yl)-2-(2-methoxy-ethyl)-2H-pyridazin-3-one and 2-chloro-4-trimethylsilanylethynyl-pyridine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:18](O)[CH:19]([O:25][CH:26]([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])=O)(C)(C)C.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:18][CH:19]([O:25][CH:26]([CH3:27])[CH3:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CCOC(=O)C(OC(C)C)C(O)c1ccc(OC)c(CNC(=O)OC(C)(C)C)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reaction time: 38 h
Yield: 73.3 %

Procedure:
24.7 g of Ethyl 3-(3-[(t-butoxycarbonyl)amino]methyl-4-methoxyphenyl)-3-hydroxy-2-isopropoxypropanoate (mixture of erythro form and threo form) was dissolved in 400 ml of trifluoroacetic acid, and 96 ml of triethylsilane was added, and the mixture was stirred for 38 hours. The solvent was evaporated, and the residue was dissolved in 300 ml of 3N hydrochloric acid and 200 ml of hexane. The aqueous layer was washed with 100 ml of hexane, basified with 5N sodium hydroxide solution, and extracted with dichloromethane (200 ml×4). The organic layers were combined and dried over anhydrous magnesium sulfate, to give 13.0 g of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:29])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:38](B(O)O)[CH2:39][CH2:40][CH3:41].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1(P([Pd](Cl)(Cl)P(C2CCCCC2)(C2CCCCC2)C2CCCCC2)(C2CCCCC2)C2CCCCC2)CCCCC1.O>[CH2:38]([C:2]1[C:3]([CH3:29])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)(=[O:20])=[O:21])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCB(O)O
Reactant: Cc1c(Br)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[PH](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)O)c1C
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A mixture of Example 225A (123 mg, 0.26 mmol), potassium phosphate (192 mg, 0.9 mmol), butylboronic acid (34 mg, 0.33 mmol), bis(tricyclohexylphosphino)palladium dichloride (19 mg, 0.03 mmol), toluene (4 mL), and water (0.2 mL) was purged with argon and shaken at 100° C. for 36 hours in a sealed container. The mixture was diluted with ethyl acetate (10 mL), washed with water (2×10 mL) and brine, dried (Na2SO4), filtered, concentrated and passed through a silica gel cartridge (20 g) with 15% ethyl acetate/hexanes. The isolated solid was substituted for Example 108C in Example 108D and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired-product. MS (ESI(+)) m/e 383 (M+NH4)+; (ESI(−)) m/e 364 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.09 (br s, 1H), 9.74 (br s, 1H), 7.78 (m, 2H), 7.39 (m, 2H), 7.08 (d, 1H), 6.71 (d, 1H), 2.55 (q, 2H), 2.18 (s, 3H), 1.44 (m, 2H), 1.32 (m, 2H), 0.91 (t, 3H).