Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH2:19])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH:29]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30]1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:33]([CH:29]3[CH2:32][CH2:31][CH2:30]3)(=[O:35])=[O:34])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Reactant: O=S(=O)(Cl)C1CCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2)C1CCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanamine (120 mg, 0.286 mmol), para-(N,N-dimethylamino) pyridine (1.40 g, 19.7 mmol), and cyclobutanesulfonyl chloride (46.5 mg, 0.30 mmol) were dissolved in CH2Cl2 (20 ml) and stirred for 14 h at room temperature. 0.5N HCl was added, the organic phase separated and the aqueous phase extracted with CH2Cl2. The combined organic layers were washed with water, NaHCO3 solution, and saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl2 3:97→5:95). The white solid product (164 mg, 32%) was trans-ferred to an HCl salt and precipitated from diisopropyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of 48.8 g of methyl 4-[(E)-2-(4-nitrophenyl)vinyl]benzoate, 600 mL of THF, and 200 mL of N,N-dimethylformamide (DMF) was added 10.0 g of 10% palladium on carbon (wetted with 55% H2O), followed by stirring at room temperature for 8 hours under a hydrogen atmosphere (1 atm). The inside of the reaction container was replaced with argon, and then the insoluble materials were filtered off on a celite layer. The filtrate was concentrated under reduced pressure, and to the residue was added 1000 mL of water, followed by stirring at room temperature for 30 minutes. The precipitate was collected by filtration to obtain 43.3 g of methyl 4-[2-(4-aminophenyl)ethyl]benzoate as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[S:10][C:6]=2[CH:5]=1)([O-])=O.CN(C)C=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[S:10][C:6]=2[CH:5]=1
Reactant: O=C(Nc1nc2ccc([N+](=O)[O-])cc2s1)c1ccncc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc2nc(NC(=O)c3ccncc3)sc2c1
Yield: 79.6 %

Procedure:
N-(6-Nitrobenzothiazol-2-yl)isonicotinamide (2.42 g, 8.04 mmol) was suspended in ethyl acetate (150 mL), and dimethylformamide was added until dissolution occured. After addition of palladium on charcoal (4.25 g, 10% Pd, 4 mmol Pd) the mixtue was hydrogenated (1 bar) at 60° C. until completion of the reaction. The palladium was removed by filtration through a pad of celite and the solvent was evaporated. The residue was taken up in little methanol and precipitated by addition of water to obtain N-(6-aminobenzothiazol-2-yl)isonicotinamide (1.73 g, 6.4 mmol, 80%). LC/ESI-MS: m/z=271 [M+H]+; m/z=269 [M−H]−; Rt=1.43 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>>[C:20]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)(=[O:23])[CH2:21][CH3:22]
Reactant: Cc1ccc2c(=O)n3c(nc2c1)[nH]c1ccccc13
Reactant: CCC(=O)Cl
Product: CCC(=O)n1c2ccccc2n2c(=O)c3ccc(C)cc3nc12

Procedure:
6-Propionyl-3-methylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-methylbenzimidazo[2,1-b]quinazolin-12(6H)one and propionyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C1CCC(N=C=NC2CCCCC2)CC1.Cl>C(OCC)(=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[C:15]([O:14][C:13]([F:12])([F:22])[F:23])[CH:16]=2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(C(=O)Nc2cccc(OC(F)(F)F)c2)cc1
Temperature: 60 °C
Yield: 38 %

Procedure:
to a solution of 300 mg of 4-carboxybenzaldehyde (2 mmoles) and 382 mg of 3-(trifluoromethoxy)aniline (2 mmoles) in 5 ml of ethyl acetate is added 830 mg of dicyclohexycarbodiimide (DCC) (4 mmoles). The reaction mixture is heated at 60° C. overnight and then poured into 60 ml of 1 N HCl solution. The mixture is extracted twice with 30 ml of ethyl acetate. The combined organic extracts are washed with 50 ml of water, 50 ml of a saturated solution of sodium bicarbonate and brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel giving 233 mg of 4-Formyl-N-(3-trifluoromethoxy-phenyl)-benzamide (yield=38%). Analytical LC/MS method A: ([M+H]+): 310, RT: 5.60 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH2:14]>O1CCOCC1.C(N(CC)C(C)C)(C)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:11]([Cl:10])[CH:12]=2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Cl)nc(Nc2ccc(Cl)c(Cl)c2)n1
Reaction time: 3 h
Yield: 21.7 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (5.00 g), 3,4-dichloroaniline (4.45 g, 1 equivalent) in 1,4-dioxane (20 mL) and N,N-diisopropylethylamine (10 mL) was heated at reflux with stirring for 3 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of cyclohexane to ethyl acetate/cyclohexane (1:9). The eluent was removed, giving 4,6-dichloro-N-(3,4-dichlorophenyl)-2-pyrimidinamine (1.83 g, 58%, Rf=0.39 in ethyl acetate/cyclohexane, 2:3).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:15]([O:17]CC)=[CH2:16])[C:12]=3[O:13][CH3:14])[N:8]=2)[CH2:3][CH2:2]1.O.[Br:24]N1C(=O)CCC1=O>O1CCCC1>[Br:24][CH2:17][C:15]([C:11]1[C:12]([O:13][CH3:14])=[C:6]2[O:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:8][C:7]2=[C:9]([C:21]#[N:22])[C:10]=1[CH3:20])=[O:16]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1OC
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(=O)CBr)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
2-Cyclopropyl-6-[1-(ethoxy)ethenyl]-7-methoxy-5-methyl-1,3-benzoxazole-4-carbonitrile (I-84) (2.58 g, 8.46 mmol) was dissolved in tetrahydrofuran (130 ml), water (7.7 ml) and N-bromosuccinimide (1.61 g, 8.89 mmol) were added all at a time, followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was evaporated away under reduced pressure, followed by dilution with ethyl acetate and by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography (covering) and eluted with a mixed solvent of n-hexane/ethyl acetate (2:1, v/v) to obtain the entitled compound (2.40 g, 81%) as a yellow white solid.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:19][N:20]([CH2:31][C:32]2[CH:48]=[CH:47][C:35]([CH2:36][NH:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.C(OCC)C>Br.CC(O)=O>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][N:20]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:36][NH:37][S:38]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)(=[O:40])=[O:39])=[CH:47][CH:48]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(NCc1ccc(CN(Cc2nc3ccccc3n2S(=O)(=O)c2ccccc2)C2CCCc3cccnc32)cc1)c1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=S(=O)(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccc1

Procedure:
A solution of N-(4-{[(1-benzenesulfonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-benzenesulfonamide (AMD9830) (161 mg, 0.234 mmol) in saturated HBr/AcOH (3 mL) was stirred at room temperature for 3.5 h, then diethyl ether (20 mL) was added to give a colourless precipitate. The supernatant was decanted, and the residue was partitioned between CH2Cl2 (10 mL) and saturated NaHCO3(aq) (15 mL). The basic aqueous phase was extracted with CH2Cl2 (10 mL), and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (500:5:1 CH2Cl2/MeOH/NH4OH) gave AMD9845 (59 mg, 44%) as a yellow foam. 1H NMR (CDCl3) δ 1.68 (m, 1H), 1.99 (m, 2H), 2.24 (m, 1H), 2.67-2.91 (m, 2H), 3.68 (s, 2H), 3.86 (d, 1H, J=17 Hz), 4.05 (m, 3H), 4.14 (d, 1H, J=17 Hz), 4.87 (m, 1H), 7.01 (d, 2H, J=7.8 Hz), 7.18 (m, 3H), 7.28 (m, 2H), 7.37-7.60 (m, 6H), 7.80 (m, 2H), 8.68 (m, 1H); 13C NMR (CDCl3) δ 22.08, 24.18, 29.90, 47.66, 49.21, 54.47, 61.26, 122.30, 123.03, 127.75, 128.54, 129.65, 129.73, 133.29, 135.47, 135.74, 138.01, 139.87, 140.65, 147.63, 156.87, 158.03. ES-MS m/z 538 (M+H). Anal. Calcd. for C31H31N5SO2.0.46CH2Cl2: C, 65.52; H, 5.58; N, 12.14. Found: C, 65.56; H, 5.60; N, 12.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14]>ClCCl.CO>[NH2:19][C:17]1[CH:16]=[CH:15][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][OH:14])=[C:3]([O:2][CH3:1])[CH:18]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC[C@H]1CO
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1CCC[C@H]1CO

Procedure:
Prepared analogously to Example 3.1.b. from {(S)-1-[2-(2-methoxy-4-nitrophenoxy)ethyl]pyrrolidin-2-yl}methanol. Yield: 0.15 g (83.4% of theory); C14H22N2O3 (M=266.34); calc.: molecular ion peak (M+H)+: 267; found: molecular ion peak (M+H)+: 267; Rf value: 0.15 (silica gel, dichloromethane/methanol 9:1)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[K+].CO.[C:18](=S)=[S:19]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:18]([SH:19])=[N:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NNC(=O)c1ccc2c(c1)OCO2
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Sc1nnc(-c2ccc3c(c2)OCO3)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzo[1,3]dioxole-5-carboxylic acid hydrazide (45.8 g, 254 mmol) was added to a mixture of potassium hydroxide (15.7 g, 280 mmol) and methanol (350 ml). The mixture was stirred for 30 minutes at room temperature. Carbon disulfide (38.7 g, 508 mmol) was added. The mixture was stirred at reflux for 20 hours, followed by another portion of carbon disulfide (12.7 g, 167 mmol) and reflux for 4 h. Water (300 ml) was added and the excess of carbon disulfide and methanol was evaporated. The aqueous suspension was acidified by adding concentrated hydrochloric acid to pH 3-4. The product precipitated, filtered and was washed with water (50 ml). Yield 53.5 g (95%) as yellow powder.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(OCC)(=O)C.[Pd]>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)O
Reaction time: 6 h

Procedure:
In the hydrogenation vessel, oleic acid (10 g, 35.4 mmol) were dissolved in 50 ml ethyl acetate. 1 g of 5% Pd—C were added and the vessel was connected to the hydrogenation apparatus and pressure was set at 50 psi for 6 hours. At the end of this period white precipitate of stearic acid was formed. To ensure total solubilization of stearic acid, 400 ml of ethyl acetate were added and the black precipitate was filtered out and washed with additional 100 ethyl acetate. The filtrate was removed which gave stearic acid in quantitative yield.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[ClH:9].[CH3:10][C:11]1[N:12]=[C:13]([NH:16][C:17]2[CH:25]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=2)[S:14][CH:15]=1>>[ClH:9].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:21]([C:20]2[CH:19]=[N:18][C:17]([NH:16][C:13]3[S:14][CH:15]=[C:11]([CH3:10])[N:12]=3)=[CH:25][C:24]=2[O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:22])[CH2:5][CH2:4]1)[CH3:2]
Reactant: Cc1csc(Nc2cc(Oc3ccccc3)c(C(=O)O)cn2)n1
Reactant: CCN1CCNCC1
Agent: Cl
Product: CCN1CCN(C(=O)c2cnc(Nc3nc(C)cs3)cc2Oc2ccccc2)CC1

Procedure:
Prepared according to the method of Example 32 from 1-ethylpiperazine and 6-(4-methylthiazol-2-ylamino)-4-phenoxynicotinic acid hydrochloride (Example 59). Yield: 0.055 g, 43.07%. 1H NMR (CDCl3) δ 8.34 (s, 1H), 7.47 (t, 2H), 7.33 (t, 1H), 7.06 (s, 1H), 7.04 (s, 1H), 6.38 (s, 1H), 6.26 (s, 1H), 3.97 (m, 3H), 2.97 (m, 7H), 2.27 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CS(C)=O>[CH3:33][NH:32][C:28]1[N:27]=[C:26]([C:25]2[C:20]([O:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:31]=[CH:30][N:29]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(N4CCOCC4)c4ccccc34)cc2)n1
Temperature: 100 °C

Procedure:
To a resealable tube was added 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.263 mmol) and DMSO (0.526 mL, 0.5 M). To this solution was added morpholine (0.689 mL, 7.89 mmol) and TEA (0.037 mL, 0.26 mmol), and the reaction mixture was heated at 100° C. for 48 h. The reaction was cooled and concentrated under reduced pressure. The crude residue was dissolved in dichloromethane and purified by Biotage column chromatography on silica gel (1%-5% MeOH/Dichloromethane); which provided pure N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-morpholinophthalazin-1-amine as a yellow solid. MS m/z=507 [M+H]+. Calc'd for C28H26N8O2: 506.56.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[N:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][O:9][C:8]1[C:3]([CH2:2][N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:4][CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1nc(-c2ccccc2)cnc1CCl
Reactant: c1c[nH]c(-c2nccs2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2)cnc1Cn1ccnc1-c1nccs1
Temperature: 45 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
A mixture of 2-chloromethyl-3-methoxy-5-phenyl-pyrazine (90 mg, 0.38 mmol; prepared as described above), 2-(1H-imidazol-2-yl)-thiazole (55 mg, 0.363 mmol) and K2CO3 (159 mg, 1.15 mmol) in DMF (7 mL) is stirred at 45° C. for 16 hours. On cooling, the reaction is quenched with saturated NH4Cl (3 mL) and extracted with DCM (3×15 mL). The combined organic layers are dried and solvent removed. PTLC separation (silica gel; 10% MeOH in DCM) gives 78 mg of 3-methoxy-5-phenyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-pyrazine as an oil. 1H NMR (CDCl3) 8.47 (s, 1H), 7.97–8.01 (m, 2H), 7.76 (d, 1H), 7.42–7.49 (m, 3H), 7.28 (d, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 6.03 (s, 2H), 4.05 (s, 3H)
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-])=O)=[C:9]([CH:12]=1)[CH:10]=O.O=[C:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:4][C:5]1[CH:12]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:13]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([CH3:24])=[CH:10]2
Reactant: CCOC(=O)C(=O)CC
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1nc2ccc(Br)cc2cc1C
Temperature: 70 °C
Yield: 17.6 %

Procedure:
A 2.2 M solution of zinc(II)chloride (6.05 mL, 13.32 mmol) in diethyl ether was added to tin(II)chloride (2.53 g, 13.32 mmol) and activated 4 Å molecular sieve pellets (612.8 mg) under argon. Then, 5-bromo-2-nitro-benzaldehyde (612.8 mg, 2.66 mmol) and ethyl 2-oxobutanoate (346.7 mg, 2.66 mmol) in ethanol (13 mL) were added to the reaction mixture via canula. The mixture was heated at 70° C. in an oil bath for three hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 137.9 mg (18%) of ethyl 6-bromo-3-methyl-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 8.30 (s, 1H), 8.27 (d, J=2 Hz, 1H), 7.99 (d, J=9 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 4.41 (q, J=7 Hz, 2H), 2.54 (s, 3H), 1.35 (t, J=7 Hz, 3H). ESI-LCMS m/z 294 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][Br:12]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1CBr
Temperature: 80 °C
Reaction time: 16 h
Yield: 102.8 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1-bromo-2-methyl-3-nitrobenzene (6.86 g, 31.8 mmol) and carbon tetrachloride (40 mL) and heated to 80° C. N-bromo-succinimide (6.96 g, 39.1 mmol) and 2,2′-azobis(2-methylpropionitrile) (522 mg, 3.18 mmol) were added, and the reaction mixture was stirred at 80° C. for 16 h. After this time, the reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with methylene chloride (20 mL). The filtrate was concentrated under reduced pressure to afford crude 114a (9.64 g, 103% crude yield) as a yellow oil, which was used directly in the next step: 1H NMR (500 MHz, CDCl3) δ 7.89-7.86 (m, 2H), 7.35 (t, 1H, J=8.0 Hz), 4.89 (s, 2H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[N:28][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=2)=[N:30][CH:31]=1>[Cl-]>[Cl:25][C:26]1[CH:31]=[N:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=[C:1]([Br:5])[Br:2])[CH:34]=2)=[N:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cccc(Oc2ncc(Cl)cn2)c1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1cnc(Oc2cccc(C=C(Br)Br)c2)nc1
Yield: 100.2 %

Procedure:
Carbon tetrabromide (3.32 g) was added with stirring to a solution of triphenylphosphine (5.24 g) in methylne chloride (20 ml) at 20° C. 5-Chloro-2-(3-formylphenoxy)-pyrimidine (1.8 g) was added immediately to the warm orange solution causing the colour to fade rapidly. After 2 hours at 20° C. the reaction mixture was washed with water and then the organic layer was dried and concentrated to a thick syrup. Extraction of this syrup with n-hexane (4×50 ml), followed by evaporation of the n-hexane gave a colourless oil (3 g). The oil was chromatographed on a column of silica gel (50 g) and elution with chloroform gave the title compound, in the first fractions, as a colourless crystalline solid (1.95 g), m.p. 68° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]([CH2:12][CH2:13][CH2:14][CH2:15]Br)[C:7](=[O:17])[C:6]=2[CH:18]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[S:9]2(=[O:11])=[O:10])[CH2:27][CH2:26]1
Reactant: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2S(=O)(=O)N1CCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of 5-fluoro-2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)one 1,1-dioxide and 0.02 mol of 1-(2-pyrimidinyl)piperazine are stirred with 0.02 mol of K2CO3 in 150 ml of absolute DMF at 100° C. for 1 hour. The mixture is then evaporated. Water is added and the organic substance is taken up in methylene chloride. The dried CH2Cl2 phase is applied to a silica gel column and eluted with CH2Cl2 /CH3OH (95:5).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:26])([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[S:35]([N:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:26])([C:14]([F:16])([F:17])[F:15])[C:18]#[C:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:9][CH:8]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: OC(C#Cc1ccccc1)(c1ccc(NC2CCCC2)cc1)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N(c1ccc(C(O)(C#Cc2ccccc2)C(F)(F)F)cc1)C1CCCC1
Temperature: 70 °C

Procedure:
A mixture of 53 mg of 2-(4-cyclopentylamino-phenyl)-1,1,1-trifluoro-4-phenyl-but-3-yn-2-ol (0.15 mmol) and 44 mg of 2,5-dichlorobenzenesulfonyl chloride (0.18 mmol) in 0.2 ml of pyridine was heated to 70° C. for 14 hours. After this time the reaction mixture was allowed to cool to room temperature, quenched by the addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica (hexanes:EtOAc, 4:1) to give the title compound. 1H-NMR (CDCl3) δ 1.36-1.58 (m, 6H), 1.97-2.07 (m, 2H), 4.73-4.78 (m, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.37-7.55 (m, 7H), 7.76 (d, J=8.4 Hz, 2H), 7.84 (d, J=2.4 Hz, 1H). Mass Spectrum (CI+) m/e=590.0 (M+23).