Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:23])[C:11]2[C:16]([C:17]=1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl.C(#N)C>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:23])[C:11]2[C:16]([C:17]=1[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cncs1
Reactant: BrP(Br)Br
Solvent: CC#N
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cncs1
Yield: 44.8 %

Procedure:
1M PBr3 (0.5 ml, 0.50 mmol) in DCM was added drop-wise to of 3-(1-hydroxyethyl)-4-(thiazol-5-yl)-1H-isochromen-1-one (Intermediate B11, 102 mg, 0.372 mmol) in DCM (4 ml) and ACN (2 ml) at RT. Reaction mixture was then concentrated under reduced pressure and straightforward purified on Biotage Silica SNAP 12 g cartridge with a gradient of hexane and EtOAc to give the title compound (56 mg, 45%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[CH2:8][CH2:7][C:5]=2[CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:11][C:4]1[CH:3]=[CH:2][CH:1]=[C:6]2[C:5]=1[CH2:7][CH2:8][C:9]2=[O:10]
Reactant: O=C1CCc2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(O)cccc21
Temperature: 200 °C
Yield: 41.5 %

Procedure:
Dihydrocoumarin (35 g, 0.236 mol) was added to 62.9 g (0.472 mol) of aluminum chloride and the mixture was heated in an oil-bath at 200° C. for 2.5 h with stirring The reaction mixture was cooled, poured into ice (300 g), 300 ml of methylene chloride added to the mixture, cooled, and 400 ml of methylene chloride was added. The mixture was filtered and the solid residue was dissolved in hot methanol, filtered, and the filtrate was cooled to afford 14.5 g (41%) of 4-hydroxy-indan-1-one.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH3:15])[CH2:10][C:11]([NH:23][CH2:20][CH2:21][CH3:22])=[O:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2]
Reactant: CCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: CCCN
Product: CCCNC(=O)CN(CC)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 3 using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-ethylglycine and propylamine: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.8 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.77 (dd, J=8.8, 2.4 Hz, 1H), 5.99 (bs, 1H), 3.96 (s, 2H), 3.54 (q, J=7.1 Hz, 2H), 3.47 (q, J=7.0 Hz, 2H), 1.46 (m, 2H), 1.25 (t, J=7.1 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][S:9]([O:12][CH2:13][CH2:14][N:15]1[C:19]([NH2:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[N:16]1)(=[O:11])=[O:10].C(OC(C)C)(C)C>C(O)=O>[CH3:8][S:9]([O:12][CH2:13][CH2:14][N:15]1[C:19]([NH:20][CH:1]=[O:3])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[N:16]1)(=[O:10])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1N
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1cnn(CCOS(C)(=O)=O)c1NC=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of acetic anhydride (184 ml) and formic acid (93 ml) was stirred for 30 minutes at room temperature. The mixture was cooled at 5° C. with ice-bath and added to 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-aminopyrazole (270 g). The mixture was stirred for 3 hours under ice-cooling. The reaction mixture was evaporated to give crystals. To the crystals was added diisopropyl ether and the mixture was stirred for 1 hour. The crystals were collected by filtration to give 1-(2-methylsulfonyloxyethyl)-4-ethoxycarbonyl-5-formamidopyrazole (291.5 g).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH:17]([F:19])[F:18].[Li]CCCC.CN([CH:28]=[O:29])C.[NH4+].[Cl-]>C1COCC1>[F:18][CH:17]([F:19])[C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:15]=[CH:16][C:2]=1[CH:28]=[O:29]
Reactant: FC(F)c1cc(OCCN2CCOCC2)ccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCOCC2)cc1C(F)F
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of 4-(2-(4-bromo-3-(difluoromethyl)phenoxy)ethyl)morpholine (123; 2.8 g, 8.38 mmol) in THF (90 mL) was added n-BuLi (1.6 M solution in hexanes, 7 mL, 11.2 mmol) at −78° C. The resulting reaction mixture was stirred at the same temperature for 1 h and DMF (1.24 g, 17 mmol) was added dropwise. After stirring the mixture at −78° C. for an additional 30 min, saturated aqueous NH4Cl was added and the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography afforded 2-(difluoromethyl)-4-(2-morpholinoethoxy)benzaldehyde 124 (1.6 g, 67%) as a brown yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[C:44]([O:48][CH3:49])(=[O:47])[CH:45]=[CH2:46]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:46]=[CH:45][C:44]([O:48][CH3:49])=[O:47])[CH3:9]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1ccccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C

Procedure:
(2R)-2-[[(1R)-1-(2-Bromophenyl)ethoxy]methyl]oxirane (1.00 g) obtained in Step 1 was dissolved in acetonitrile (10 ml), palladium acetate (II) (45 mg), tri-o-tolylphosphine (63 mg), triethylamine (0.65 ml) and methyl acrylate (0.42 ml) were added, and the mixture was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, and, after filtration through celite, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (203 mg).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si](Cl)(C)C>C1COCC1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2]1
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
Into a 1 L round-bottom flask was placed a solution of cyclohex-2-en-1-one (15.00 g, 156.04 mmol, 1.00 equiv) in anhydrous THF (300 mL). 1,3-diethyl 2-bromopropanedioate (56.00 g, 234.25 mmol, 1.50 equiv), In powder (18.00 g, 1.00 equiv) and TMSCl (87.00 g, 800.81 mmol, 5.00 equiv) were added under nitrogen. The resulting solution was stirred for 30 min at room temperature and quenched by the addition of 200 mL of saturated aqueous sodium carbonate, extracted with 3×300 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to give 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate (28.50 g, 71%) as a yellow oil.
Reaction SMILES: Br.C(O)(=O)C.C(OC([NH:16][CH2:17][CH:18]1[CH2:21][N:20]([C:22]2[S:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=2)[CH2:19]1)=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)(=O)C>[NH2:16][CH2:17][CH:18]1[CH2:21][N:20]([C:22]2[S:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:25]([CH3:27])[N:26]=2)[CH2:19]1
Reactant: CCOC(=O)c1sc(N2CC(CNC(=O)OCc3ccccc3)C2)nc1C
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(N2CC(CN)C2)nc1C
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 60.5 %

Procedure:
A 30% hydrogen bromide/acetic acid solution (0.64 mL, 3.29 mmol) was added to a solution of ethyl 2-[3-({[(benzyloxy)carbonyl]amino}methyl)azetidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (233b) (128 mg, 0.33 mmol) in acetic acid (1 mL), and the mixture was stirred at room temperature for 100 minutes. A 1 N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the filtrate was concentrated under reduced pressure to obtain 51 mg of the title compound as a colorless oily substance (61%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[O:11][C:10](=[O:13])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:15][C:16]([NH2:18])=[O:17]>CN(C=O)C>[F:3][C:4]1[C:12]2[O:11][C:10](=[O:13])[N:9]([CH2:15][C:16]([NH2:18])=[O:17])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)CBr
Reactant: O=c1[nH]c2cccc(F)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1c(=O)oc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, NaH (in oil, 60 w/w, 1.8 g, 45.15 mmol) is carefully added by portion into a solution of 7-fluoro-1,3-benzoxazol-2(3H)-one 2 (5.76 g, 37.62 mmol) in dried DMF (80 ml) at 0° C. After 0.25 h, 2-bromo-acetamide (6.22 g, 45.15 mmol) is added. The reaction mixture is stirred for 1 h at room temperature, quenched with water, concentrated in vacuo and the residue is recrystallized in EtOH/H2O (80/20 (v/v)) to afford 2-(7-fluoro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15]C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:28]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:17](=[O:19])[NH:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH2:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: CCCCC(NC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
19.7 g of N-carbobenzoxy-DL-norleucine are dissolved in 200 ml of absolute tetrahydrofuran, the solution is treated dropwise while cooling with ice with 10 g of thionyl chloride and then stirred for 1 hour. To this solution there is rapidly added dropwise a solution of 17 g (0.065 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 130 ml of absolute tetrahydrofuran and the mixture is then stirred at room temperature for 60 hours. The solution is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 450 g silica gel column using methylene chloride as the eluting agent and crystallised from ethanol. There is obtained benzyl-rac-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]butyl}carbamate which melts at 148°-150° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1.[H-].[Na+].I[CH2:23][CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]>CN(C)C=O.O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](=[O:18])[N:14]([CH2:23][CH2:24][O:25][Si:26]([CH:30]([CH3:31])[CH3:32])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])[C:13]=2[CH:19]=1
Reactant: O=C1COc2ccc(COC3CCCCO3)cc2N1
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)[Si](OCCN1C(=O)COc2ccc(COC3CCCCO3)cc21)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
The solution of 5.50 g of 6-(tetrahydropyran-2-yloxymethyl)-4H-benzo[1,4]oxazin-3-one and 100 ml of N,N-dimethylformamide-tetrahydrofuran (1:1) is cooled to 0° C., admixed with 0.800 g of sodium hydride dispersion (60%) and stirred over 30 minutes. The mixture is admixed with 7.90 g of (2-iodoethoxy)triisopropylsilane and stirred at room temperature for a further 16 hours. The reaction mixture is poured onto ice-water (150 ml) and extracted with ethyl acetate (3×150 ml). The organic phases are washed successively with aqueous sodium hydrogencarbonate solution (1×100 ml), water (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.57 (1:1 EtOAc-heptane); Rt=6.71.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[N:12]=[CH:13][C:14]4[C:19](=[O:20])[N:18]5[N:21]=[CH:22][CH:23]=[C:17]5[NH:16][C:15]=4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][CH2:26][CH2:27]Br>>[C:1]1([N:7]2[C:11]3[N:12]=[CH:13][C:14]4[C:19](=[O:20])[N:18]5[N:21]=[CH:22][CH:23]=[C:17]5[N:16]([CH2:27][CH2:26][O:25][CH3:24])[C:15]=4[C:10]=3[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCBr
Reactant: O=c1c2cnc3c(cnn3-c3ccccc3)c2[nH]c2ccnn12
Product: COCCn1c2c(cnc3c2cnn3-c2ccccc2)c(=O)n2nccc12

Procedure:
By treating the product of Example 23 with methoxyethyl bromide instead of 1-bromo-3-methylbutane according to the procedure of Example 2,3-phenyl-3,11-dihydro-11-methoxyethyl-6H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[4,3-d]pyrimidin-6-one is obtained.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([NH:10][N:11]=[C:12]([CH3:16])[C:13](O)=[O:14])(=[S:9])[NH2:8].Cl>O>[CH3:16][C:12]1[C:13](=[O:14])[NH:8][C:7](=[S:9])[NH:10][N:11]=1
Reactant: CC(=NNC(N)=S)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1n[nH]c(=S)[nH]c1=O
Temperature: 25 °C

Procedure:
To a solution of Na2CO3 (4.84 g, 45.6 mmol) in water (300 mL) was added 2-(2-carbamothioylhydrazono)propanoic acid (3, 7.35 g, 45.6 mmol). The mixture was heated at refluxing temperature for 3.5 h. After cooling to room temperature, the clear solution was acidified with 2 N HCl to pH ˜5. The mixture was extracted with EtOAc (60 mL×4) and CH2Cl2 (60 mL×4). The combined extracts were dried over Na2SO4 and concentrated to give 6-methyl-3-thioxo-3,4-dihydro-1,2,4-triazin-5(2H)-one (4) as a white solid. MS: m/z, 144 (100%, M+1).
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=[S:8])([CH3:5])[CH3:4]>C(O)=O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:7]4[S:8][CH2:2][C:3]([CH3:4])([CH3:5])[N:6]=4)=[CH:11][CH:12]=3)[CH2:17][CH2:18]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=S)NC(C)(C)CO)cc3)CC2)cc1
Solvent: O=CO
Product: COc1ccc(N2CCN(c3ccc(NC4=NC(C)(C)CS4)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.4 %

Procedure:
A mixture of 74 parts of N-(2-hydroxy-1,1-dimethylethyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea and 360 parts of formic acid was stirred for 4 hours at 70° C. The reaction mixture was evaporated and the residue was dissolved in 260 parts of dichloromethane. The whole was neutralized with a sodium hydrogen carbonate solution. The precipitated product was filtered off, washed with water and dichloromethane and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 44.1 parts (62.4%) of 4,5-dihydro-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4,4-dimethyl-2-thiazolamine; mp. 232.0° C. (int. 8).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[N:6][N:5]2[C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[CH:22]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[N:6][N:5]2[C:20]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)c(N)nc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)c(N)nc3c2)c1

Procedure:
3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo-[1,2-b]-pyridazin-7-yl]-N-methyl benzamide (1 eq, 0.146 mmol, 79 mg) and phenyl boronic acid (1.5 eq, 0.219 mmol, 27.5 mg) are dissolved in DME (1.5 ml) and water (0.4 ml) and Na2CO3 (3 eq, 0.438 mmol, 46.4 mg) are added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.12 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 3-(2-Amino-3-(2-phenyl-pyridin-4-yl)imidazo [1,2-b]pyridazin-7-yl]-N-methyl-benzamide as a yellow solid; [M+H]+=421
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([CH3:15])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]1[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>O.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([C:11]([F:13])([F:12])[F:14])=[C:9]([CH3:15])[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:7]1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)c(C)c(C(F)(F)F)n1Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)O)n(Cc2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Yield: 112.1 %

Procedure:
To a mixture of ethyl 1-(3-chlorobenzyl)-3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (737 mg, 1.6 mmol) in H2O (10 mL) and EtOH (10 mL) was added NaOH (1.29 g, 32 mmol) and the mixture stirred at reflux for 3 h. The reaction mixture cooled to room temperature and concentrated the next day. Aqueous 5N HCl was added and the solids which had been formed were filtered off and dried on air for 5 d to give 768 mg of compound ACI-05 as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:24]1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.N>CN(C)C=O>[NH2:24][C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:22]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 21.4 g of 1-tert.butyloxycarbonyl-4-(4-carboxyphenyl)-piperidine in 250 ml of anhydrous dimethylformamide are added, at -10° C., 9.5 g of 1-hydroxy-(1H)-benzotriazole and 17.3 g of N,N'-dicyclohexylcarbodiimide. The mixture is stirred for 15 minutes at -10° C. and the temperature is allowed to come up to ambient temperature within 1 hour. Then at -10° C. 20 ml of conc. ammonia are added dropwise with vigorous stirring. The mixture is stirred for 1 hour at -10° C. and for a further 2 hours at ambient temperature. The solvent is removed under reduced pressure. The residue remaining is suspended in water and the aqueous phase is extracted four times with ethyl acetate. The combined ethyl acetate phases are filtered, the filtrate is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue remaining is chromatographed over silica gel. Yield: 17.5 g (82% of theory), Melting point: 188°-191° C. Rf value: 0.36 (silica gel; ethyl acetate/cyclohexane=4:1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH2:18]([NH:20][CH:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:12][CH2:13]1)[CH3:19]
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.6 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and ethylamine (23 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile] to give an anti-form compound (10 mg) and a syn-form compound (10 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:9]2=3)[C:5](=O)[NH:4][C:3]1=[O:25].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:9]2=3)[C:5](=[S:35])[NH:4][C:3]1=[O:25]
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (i) (0.2 g) and Lawesson's reagent (0.29 g) according to the method of example 2 step (ii). Purification was by chromatography eluting with 50% acetone in isohexane followed by trituration with isohexane/ethyl acetate.
Reaction SMILES: Cl[CH:2](Cl)/[C:3](=[N:5]\[NH:6]S(C1C=CC(C)=CC=1)(=O)=O)/[CH3:4].C(N(CC)CC)C.[C:25]([Si:29]([CH3:35])([CH3:34])[O:30][CH2:31][CH2:32][NH2:33])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([Si:29]([CH3:35])([CH3:34])[O:30][CH2:31][CH2:32][N:33]1[CH:2]=[C:3]([CH3:4])[N:5]=[N:6]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCN
Reactant: C/C(=N/NS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cn(CCO[Si](C)(C)C(C)(C)C)nn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a suspension of N′-[(1Z)-2,2-dichloro-1-methylethylidene]-4-methylbenzenesulfonohydrazide (prepared according to WO2007088478 example 13) (5.0 g, 16.9 mmol) in methanol (100 mL), at 0° C. under an atmosphere of nitrogen, was added triethylamine (11.8 mL, 84.7 mmol, 5.0 eq.) over a period of 2 min. To the resulting orange solution was added a solution of 2-{[tert-butyl-(dimethyl)silyl]oxy}ethanamine (prepared according to J.O.C. 74(4), 1791-1793, 2009) (3.3 g, 18.8 mmol, 1.1 eq.) in methanol (70 ml). The reaction mixture was stirred at room temperature for 18 hr. The mixture was then evaporated under reduced pressure and the residue partitioned between tert-butyl methyl ether (250 mL) and aqueous citric acid (10% wt/vol, 100 mL). The organic phase was washed with aqueous sodium hydrogen carbonate (1M, 100 mL), saturated brine (20 mL) and dried over sodium sulphate. The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give a crude brown oil. The crude oil was purified by chromatography on silica gel (200 g) eluting with a gradient of tert-butyl methyl ether in toluene (10:90 to 40:60) to give the title compound as a yellow oil (3.07 g, 75%).