Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([SH:8])[CH2:3][S:4][CH2:5][CH2:6][SH:7].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(O)C>[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][S:8][CH2:2][CH2:3][S:4][CH2:5][CH2:6][S:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCl
Reactant: SCCSCCS
Agent: [Na]
Solvent: CCO
Product: CCCCCSCCSCCSCCCCC
Reaction time: 0.5 h
Yield: 62 %

Procedure:
(Compound 1) of formula: ##STR11## 150 ml of absolute ethanol are introduced into a 500 ml three-necked flask, under argon, which is equipped with a thermometer, a condenser and a dropping funnel. Into it are dissolved 4.6 g of sodium (0.20 mole) and heating takes place to 45° C. This is followed by the slow addition of 15.43 g of an ethanolic 3-thia-1,5-pentane dithiol solution (0.10 mole). After stirring for 30 min., slow addition takes place of 25.58 g of an ethanolic 1-chloropentane solution (0.24 mole) and refluxing takes place for 4 hours. The reaction mixture is brought to ambient temperature, followed by filtering. This gives 28.8 g of crude product which is solubilized in 200 ml of dichloromethane and this is all washed with 2×100 ml of distilled water. Drying takes place on MgSO4, followed by filtration. After evaporating the solvent, recrystallization takes place twice in ethanol giving 18.21 g of 6,9,12-trithiaheptadecane, which corresponds to a 62% yield. The said thioether has the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[C:29]([F:39])=[CH:30][C:31]([F:38])=[C:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=1>>[F:38][C:31]1[CH:30]=[C:29]([F:39])[C:28]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)=[CH:33][C:32]=1[S:34]([NH2:37])(=[O:36])=[O:35]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cc(S(N)(=O)=O)c(F)cc3F)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.9) (0.40 g, 1.1 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (0.635 g, 2.3 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 27%). MS (ISP) 505.1 [(M+H)+]; mp 227° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[C:15]3[C:20]([CH:21]=[C:22]4[C:27]=2[CH:26]=[CH:25][CH:24]=[CH:23]4)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][CH:5]=1>ClCCl.C(O)C>[Br:1][C:21]1[C:22]2[C:27]([C:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([CH3:3])=[CH:5][CH:6]=3)=[C:15]3[C:20]=1[CH:19]=[CH:18][CH:17]=[CH:16]3)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: BrBr
Reactant: Cc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 18.0 ml (352 mmol) of bromine in 100 ml of dichloromethane is added dropwise with vigorous stirring to a solution of 102.0 g (320 mmol) of 9-(4-methylnaphth-1-yl)anthracene in 2000 ml of dichloromethane at −5° C., and the mixture is stirred at room temperature for 12 h. The suspension is subsequently diluted with 1000 ml of ethanol. The precipitated solid is filtered off with suction, washed with 500 ml of a mixture of water and ethanol (1:1, v:v) and three times with 200 ml of ethanol. After washing twice with 1000 ml of boiling ethanol each time, the solid is dried under reduced pressure. Yield: 108.0 g (84.9% of theory), about 97% according to 1H-NMR.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([OH:31])=O)[CH:17]=2.C(=O)=O.[CH3:35][N:36]([CH3:41])[S:37]([NH2:40])(=[O:39])=[O:38].C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([NH:40][S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])=[O:31])[CH:17]=2
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1,1′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the titled product as a pale yellow friable froth (2.0 g, 74%) of substantial purity (90%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>CN(C)C=O>[CH2:27]([O:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][C@H:15]([O:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:22])[CH2:16]1)[CH:26]=[CH2:25]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](O)C1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol are dissolved in 15 ml of dimethylformamide, and 0.3 g of sodium hydride is added. After 30 minutes, 2.4 g of allyl bromide are added dropwise. The mixture is stirred at room temperature for 5 hours. 15 ml of 1N hydrochloric acid are then added to the reaction mixture, and the mixture is washed three times with 15 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 2.4 g of 4-(cis-3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole as a yellowish oil. C20H24FNO3 (345.42), MS (ESI): 346 (M+H+)
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])(=[O:11])=[O:10])=[CH:5][N:4]=1)=[CH2:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1I.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:2]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])(=[O:10])=[O:11])=[CH:5][N:4]=1
Reactant: C=Cc1ccc(S(=O)(=O)c2ccccc2F)cn1
Reactant: Fc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(/C=C/c2ccccc2F)nc1)c1ccccc1F
Temperature: 170 °C
Yield: 57.4 %

Procedure:
2-Vinyl-5-[(2-fluorophenyl)sulfonyl]pyridine (Step 1, 50 mg, 0.19 mmol), 2-fluoroiodobenzene (46 mg, 0.207 mmol), palladium(II) acetate (2 mg, 0.01 mmol) and tri-o-tolylphosphine (12 mg, 0.039 mmol) were taken up in acetonitrile/triethylamine (0.5 mL/0.5 mL) and the reaction heated to 170° C. for 20 minutes in a Smith synthesiser microwave reactor. The reaction was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by mass-triggered preparative HPLC (Nebula) to give the title compound as a beige solid (39 mg, 57%). δH (500 MHz, d6 DMSO): 9.03 (1H, d, J=2.2 Hz), 8.28 (1H, dd, J=1.6, 8.3 Hz), 8.05 (1H, td, J=7.6, 1.6 Hz), 7.92 (1H, d, I=16.1 Hz), 7.84 (1H, td, J=8.0, 1.4 Hz), 7.80-7.74 (2H, m), 7.47 (1H, d, J=16.1 Hz), 7.47 (1H, d, =0.7 Hz), 7.42-7.36 (2H, m), 7.27-7.21 (2H, m); m/z (ES+) 358 [MH+].
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[CH:8]=[C:7](Cl)[N:6]=1>ClCCCl>[Cl:4][C:5]1[N:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:10]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: COc1cc(C(Cl)(Cl)Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
293.1 g (1.692 mol) of 30% strength sodium methylate solution were added over the course of 1½ hours to a stirred solution of 434 g (1.692 mol) of 2,6-dichloro-4-trichloromethylpyrimidine in 1 l of 1,2-dichloroethane at 0 to 5° C. The mixture was then stirred at 0 to 5° C. for 1 hour and at 25° C. for 12 hours and then extracted with water and with saturated brine. Drying over magnesium sulfate and concentration resulted in 423 g (95% of theory) of the title compound as an almost colorless oil.
Reaction SMILES: CN(C(ON1N=N[C:11]2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[CH:42]=[N:43][C:44]([N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[C:53]([C:56]([OH:58])=O)[CH:54]=3)[C:49]([S:59]([CH3:61])=[O:60])=[CH:48]2)=[N:45][CH:46]=1.[CH3:62][O:63][CH2:64][C@@H]1CCCN1>CN(C=O)C>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[N:45][C:44]([N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[C:53]([C:56]([N:15]4[CH2:14][CH2:13][CH2:12][C@H:10]4[CH2:11][CH2:62][O:63][CH3:64])=[O:58])[CH:54]=3)[C:49]([S:59]([CH3:61])=[O:60])=[CH:48]2)=[N:43][CH:42]=1
Reactant: COC[C@@H]1CCCN1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC[C@@H]1CCCN1C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
HATU (144 mg, 0.379 mmol, 1.5 eq) and diisopropylethylamine (0.13 mL, 0.759 mmol, 3.0 eq) were added at room temperature to a stirred solution of compound 51e) (100 mg, 0.253 mmol, 1.0 eq) and (S)-2-(methoxymethyl)pyrrolidine (0.02 mL, 0.303 mmol, 1.2 eq) in dry DMF (10 mL). The reaction mixture was stirred for 30 min and then diluted with ice water (20 mL). The precipitating solid was filtered off and dried. White solid. Yield: 110 mg (88% of theory). Melting range: 143-146° C. HPLC (method 1): Rt=10.03 min
Reaction SMILES: [F:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CO.C1C(=O)N(Br)C(=[O:16])C1>O>[F:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(SCF)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)CF)cc1
Yield: 87.7 %

Procedure:
(Fluoromethyl)(p-tolyl)sulfane (52.09 g, 320.06 mmol) was added to a mixture of methanol (250 mL) and water (50 mL). The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (68.36 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred at the same temperature range until the reaction was complete. After that, the reaction mixture was quenched by the addition of Na2SO3 (10%, 150 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (200 mL, 150 mL). The combined organic layer was washed with water (2×300 ml) and concentrated to ⅓ of the volume. Heptane (50 mL) was added and then removed by distillation. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 48.32 g (88%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:10][C:9]=2[F:29])=[C:5]([OH:32])[CH:4]=1)[CH3:2].O.NN.Cl>CO>[NH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:27]=[CH:28][C:8]([O:7][C:6]2[CH:30]=[CH:31][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[OH:32])=[C:9]([F:29])[CH:10]=1
Reactant: CCc1ccc(Oc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2F)c(O)c1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CCc1ccc(Oc2ccc(OCCCN)cc2F)c(O)c1
Temperature: 0 °C
Yield: 41.7 %

Procedure:
To a solution of 2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,3-dione (0.096 mmol; 42 mg) in methanol (2 mL), under argon, was added hydrazine monohydrate (0.21 mmol; 10 μL). The reaction was heated to reflux for 1 h 30. After cooling to 0° C., the mixture was hydrolysed with HCl 1N and filtered. The filtrate was basified with NaOH 0.1 N (pH=11) and extracted with chloroform (3*5 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo. The title compound (13 mg; 0.04 mmol; 44%) was obtained as yellow oil, after purification by preparative TLC (dichloromethane/methanol/NH4OH: 90/10/1).
Reaction SMILES: [Si:1]([C:8]1[C:17]([CH:18]=[O:19])=[C:16]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=[CH:15]2)[C:9]=1[CH:20]=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25].[CH:32]1([N+:38]#[C-:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCCCCC>C1C=CC=CC=1.C(OC(=O)C)C>[CH3:27][O:26][C:24]([C:23]1[C:22]([C:28]([O:30][CH3:31])=[O:29])=[C:39]([NH:38][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[O:19][C:18]=1[C:17]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:9]([CH:20]=[O:21])[C:8]=1[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[O:25]
Reactant: CC(C)(C)[Si](C)(C)c1c(C=O)c2cccccc-2c1C=O
Reactant: COC(=O)C#CC(=O)OC
Reactant: [C-]#[N+]C1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC2CCCCC2)oc(-c2c3cccccc-3c(C=O)c2[Si](C)(C)C(C)(C)C)c1C(=O)OC
Temperature: 80 °C
Reaction time: 120 h
Yield: 25.3 %

Procedure:
According to the literature procedure, a mixture of 250 mg of bis-dialdehyde 32 (0.84 mmol) and 92 mg of DMAD (dimethyl acetylenedicarboxylate) (0.84 mmol) was dissolved in 8.5 ml of anhydrous benzene and heated at 80° C. under argon. To this solution was added 119 mg of cyclohexylisocyanide (0.84 mmol) by syringe, and the heating was continued at 80° C. for further 5 days. The color of the reaction changed from red into brown. The solvent was then evaporated in vacuo, and the crude residue was purified on column chromatography using 8:2 hexane:ethylacetate to obtain first starting material, and then polarity was increased to 7:3 hexane:ethylacetate to furnish 117 mg of 50 as wine red solid in 25% yield. 1H NMR δ 10.59 (s, 1H), 9.99 (dd, 1H, J=9.9, 0.8), 8.40 (dd, 1H, J=9.9, 0.8), 7.90 (t, 1H, J=9.8), 7.71 (t, 1H, J=9.8), 7.40 (t, 1H, J=9.7), 6.72 (d, 1H, J=8.9), 3.82 (s, 3H), 3.52-3.365 (m, 1H), 3.49 (s, 3H), 1.20-2.05 (m, 10H), 0.95 (s, 9H), 0.34 (s, 3H), 0.23 (s, 3H); 13C NMR δ 189.84, 165.34, 164.39, 162.04, 157.31, 146.20, 141.70, 141.15, 139.83, 139.73, 138.19, 131.24, 130.20, 129.45, 125.96, 118.56, 86.09, 51.74, 51.35, 51.03, 34.01, 33.89, 27.34, 25.27, 24.69, 24.60, 17.95, −1.86, −3.42; LRMS (LC/MS-ESI, MeOH) m/e 550 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: Cc1cccc(CBr)n1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)n3)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
To a solution of Intermediate 2 (460 mg, 1.68 mmol) in N,N-dimethylformamide (2 mL) was added 2-(bromomethyl)-6-methylpyridine (312 mg, 1.68 mmol), potassium carbonate (350 mg, 2.53 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (100 mg, 16% yield). MS (M+H): 380
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][NH:16][CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:5].[ClH:5].[ClH:5].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][N:16]([CH:2]([CH3:4])[CH3:1])[CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:22][CH2:23]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: Cl
Reaction time: 18 h
Yield: 228.3 %

Procedure:
Acetone (0.1 ml, 1.36 mmol) was added to a solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 0.25 hours before sodium triacetoxyborohydride (500 mg, 2.4 mmol) was added, and the reaction mixture stirred for a further 18 hours. The reaction mixture was partitioned between 2N aqueous sodium hydroxide solution (10 ml) and dichloromethane (10 ml). The organic layer was evaporated under reduced pressure and purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant. The residue was dissolved in dichloromethane (2 ml) and hydrochloric acid (1M in diethyl ether, 2 ml) was added. The solvent was evaporated under reduced pressure to give the title compound as a brown foam (161 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (88 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure A to produce 29.6 mg of 110 following reverse phase hplc purification. MS (Q1) 488.3 (M)+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:17])[N:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>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.COCCOC.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:17])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:6]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[N:7]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Temperature: 90 °C
Yield: 39.1 %

Procedure:
To a suspension of mixture of methyl 2-(2,4-dichloro-6-methylpyrimidin-5-yl)pentanoate (2.56 g, 7.18 mmol) in a degassed mixture of 1,2-dimethoxyethane-water (3:1, 60 mL) were added p-tolylboronic acid (1.51 g; 10.77 mmol), tetrakis(triphenylphosphine)palladium (0.846 g; 0.732 mmol) and diisopropylethylamine (5 mL; 28.70 mmol). The resulting mixture was heated at 90° C. for 2 h. After cooling, the reaction mixture was partitioned between brine and ethyl acetate, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (3-20%) in heptane furnished 0.935 g (27%) of the title compound as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])=O.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>C(O)C>[CH2:14]([S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:16]=[C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][N:18]2[CH:2]=1)(=[O:13])=[O:12])[CH3:15]
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: CCS(=O)(=O)c1ccccc1C(=O)CBr
Solvent: CCO
Product: CCS(=O)(=O)c1ccccc1-c1cn2ccc(C(F)(F)F)cc2n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of 1.0 g of 2-bromo-2′-ethylsulfonylacetophenone, 334 mg of 2-amino-4-trifluoromethylpyridine and 4 ml of ethanol was refluxed for 1 hour and concentrated under reduced pressure. A mixture of the residue, 250 mg of sodium bicarbonate and 1.5 ml of DMF was stirred at 130° C. for 1 hour. Water was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 190 mg of 2-(2-ethylsulfonylphenyl)-7-trifluoromethyl-imidazo[1,2-a]pyridine (hereinafter, referred to as Compound of Present Invention 8).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=[N:19][OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:20][N:19]=[C:18]1[C:5]2[C:6](=[N:7][C:8]([C:9](=[O:10])[NH2:11])=[C:3]([C:1]#[N:2])[N:4]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)[CH3:33]
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CON=C1c2ccccc2-c2nc(C(N)=O)c(C#N)nc21
Temperature: 70 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To a suspension of 33 (300 mg, 1.1 mmol) and Cs2CO3 (405 mg, 1.2 mmol) in DMF (15 ml), ethyl bromoacetate (0.14 ml, 1.26 mmol) was added dropwise and the mixture was stirred at 70° C. for 24 h. The suspension was cooled at room temperature, H2O (30 ml) was added and the mixture was extracted with CH2Cl2 (70 ml). The organic phase was dried over Na2SO4 and the volatile solvent was evaporated under reduced pressure. A 1:1 mixture of n-hexane/iPr2O was added and after 2 h the obtained solid was collected by filtration. The crude was purified by flash chromatography (CH2Cl2/MeOH 85:15) affording 37 (85 mg, 22%) as green-brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.78 (bs, 1H), 8.73 (bs, 1H), 8.00 (dd, 1H), 7.82 (m, 2H), 7.67 (ddd, 1H), 4.87 (s, 2H), 4.19 (q, 2H), 1.25 (t, 3H). ESI+MS: calcd for C17H13N5O4: 351.32; found: 352.1 (MH+).