Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[N:15][N:16]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:12]([NH:29][C:30]([C:32]3[N:33]=[C:34]([CH2:37][N:38]4[CH2:43][C@H:42]([CH3:44])[O:41][C@H:40]([CH3:45])[CH2:39]4)[S:35][CH:36]=3)=[O:31])[CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[NH:46]1[CH:50]=[C:49]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[N:47]1.Cl.C(Cl)Cl>N1C=CC=CC=1>[CH3:45][C@H:40]1[O:41][C@@H:42]([CH3:44])[CH2:43][N:38]([CH2:37][C:34]2[S:35][CH:36]=[C:32]([C:30]([NH:29][C:12]3[CH:11]=[C:10]([C:4]4[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][S:51]([C:49]5[CH:50]=[N:46][NH:47][CH:48]=5)(=[O:53])=[O:52])[CH:3]=4)[CH:18]=[C:17]4[C:13]=3[CH:14]=[N:15][NH:16]4)=[O:31])[N:33]=2)[CH2:39]1
Reactant: O=S(=O)(Cl)c1cn[nH]c1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{6-[5-Amino-6-(methyloxy)-3-pyridinyl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (65 mg) was dissolved in pyridine (2 ml) and 1H-pyrazole-4-sulfonyl chloride (25 mg) was added. The reaction was stirred at RT overnight. 2M HCl (aq) (12 ml) and DCM (12 ml) were added and the reaction was vigorously stirred. The solvent was passed through a hydrophobic frit then removed under nitrogen blow down. IPA (2 ml) and 2M NaOH (aq) (1 ml) were added and the reaction was stirred at RT. The reaction was evaporated to dryness and water (1 ml) and DCM (3 ml) were added, followed by 2M HCl (aq) (1 ml). A precipitate was observed. The mixture was evaporated to dryness. The residue was purified by MDAP using the following method:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>CC(C)=O.O>[Cl:9][CH2:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:13]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1O
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCCl)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a stirred solution of 2-aminophenol (2.18 g, 20 mmol) in acetone (20 mL) a solution of 3-chloropropionyl chloride (1.28 g, 0.87 mL, 10 mmol) in acetone (20 mL) was added dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 0.5 h and then diluted with water (50 mL). Acetone was removed in vacuo, the precipitate formed was collected by filtration, washed with water, and dried to give the subtitle compound (1.53 g, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1.CC1C=CC(S(O)(=O)=O)=CC=1.CS(C)=O>O1CCOCC1>[Br:12][C:13]1[CH:14]=[N:15][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Clc1ncc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(Nc2ncc(Br)cn2)cc1

Procedure:
2-(4-Aminophenyl)acetic acid (4.56 mmol), 5-bromo-2-chloropyrimidine 4 (3.26 mmol), and p-TSA (0.842 mmol) are heated at reflux in 1,4-dioxane (10 mL) and DMSO (2 mL) for 16 h. The mixture is poured onto water and extracted with EtOAc. Concentration of the organic phase gives 2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)acetic acid 22 as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 9.84 (s, 1H), 8.58 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 3.50 (s, 2H). MS (m/z) (M+1)+: 308.0, 310.0.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)(=[O:23])=[O:22].FC(F)(F)O[C:38]1C=C(S(Cl)(=O)=O)C=C[CH:43]=1>>[CH2:38]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=3)(=[O:23])=[O:22])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:43]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-trifluoromethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=513.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3-trifluoromethoxy-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3-trifluoromethoxy-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31]>>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:25]=[CH:24][C:16]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(Cc2ccc(-c3ccc(OC[C@@H]4CCCN4)cc3)s2)cc1
Product: O=C(O)CCCN1CCC[C@H]1COc1ccc(-c2ccc(Cc3ccccc3)s2)cc1
Yield: 30 %

Procedure:
The title compound was prepared from the product of example 172 (100 mg, 0.22 mmol) and methyl 4-bromobutyrate (56 mg, 0.31 mmol) using the procedure of example 147 with 30% yield (30 mg). 1HNMR (CD3OD) 7.44 (br d, J=8 Hz, 2H), 7.32-7.20 (m, 5H), 7.01 (br d, J=3.6 Hz, 1H), 6.99 (br d, J=8 Hz, 2H), 6.73 (br d, J=3.6 Hz, 1H), 4.70 (br, 1H), 4.20 (br, 2H), 4.12 (s, 2H), 3.97 (br, 1H), 3.59 (br, 3H), 3.00 (br, 2H), 2.45 (br, 2H), 2.19-1.98 (br, 4H), LC/MS (ESI+) m/z: 92%; 437 (M+1, 100). Elemental analysis
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([N:25]4[CH2:26][CH2:27][N:22]([CH2:28][CH2:29][OH:30])[CH2:23][CH2:24]4)=[O:18])=[CH:20][CH:21]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: OCCN1CCNCC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCN(CCO)CC1
Yield: 90.2 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.15 g, 0.52 mmol) and 2-(piperazin-1-yl)ethanol (0.068 g, 0.52 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone as a white solid (0.187 g, 90.3% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12]3[C:13](=[O:20])[C:14](=[O:19])[C:15]=3OCC)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH3:21]>C(O)C>[NH2:21][C:15]1[C:14](=[O:19])[C:13](=[O:20])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: N
Reactant: CCOc1c(Nc2cccc3cnccc23)c(=O)c1=O
Solvent: CCO
Product: Nc1c(Nc2cccc3cnccc23)c(=O)c1=O
Temperature: 45 °C
Yield: 77 %

Procedure:
A suspension of the the product from Example 8, Step 1 (0.190 g, 0.700 mmol) in ethanol (3.5 mL) was saturated with ammonia, capped, and heated to 45° C. for three hours. The mixture was cooled, concentrated, and triturated with diethylether. Crude product was recrystallized from dimethylformamide/water to give 0.129 g (77%) of the title compound as a pale yellow solid, one-eighth hydrate: mp 215° C.; 1H NMR (DMSO-d6): δ9.87 (s, 1H), 9.34 (s, 1H), 8.60 (d, 1H), 7.40-8.60 (broad signal, NH2), 8.02 (d, 1H), 7.86 (d, 1H), 7.77 (d, 1H), 7.68 (t, 1H). IR (KBr): 3200, 1800, 1690, 1650 cm-1 ; MS (m/z) 240(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: OCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C

Procedure:
A mixture 3-bromobenzyl alcohol (500 mg, 2.70 mmol), 4-(triflouromethyl)benzeneboronic acid (1.01 g, 5.35 mmol), Pd(PPh3)4 (68 mg, 0.06 mmol) and Na2CO3 (740 mg, 7.02 mmol) in a mixture of DME (20 mL) and water (10 mL) was heated at reflux for 3 hours. The mixture was allowed to cool to rt, and then partitioned between EtOAc and water. The layers were separated and the aqueous re-extracted with EtOAc (2×) and the combined organic layer washed with water and then brine, dried (Na2SO4), filtered and reduced to give an oil. Purification by flash chromatography (silica) eluting with cyclohexane:EtOAc (5:2) afforded the title compound as a clear oil which crystallised on standing (654 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH:15][CH3:16])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:25][C:26]([Cl:31])([Cl:30])[C:27](Cl)=[O:28]>ClCCl>[CH3:16][NH:15][C:13](=[O:14])[C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:27](=[O:28])[C:26]([Cl:31])([Cl:30])[Cl:25])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)C(Cl)(Cl)Cl)cc2)ccn1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
The clear solution of 4-(4-aminophenoxy)-N-methylpicolinamide (100 g, 0.411 mol) in dichloromethane (100 ml) was cooled to 0° C. to −5° C. and pyridine (83 ml, 1.02 mol) was added in one lot to the reaction mass. It was then agitated at same temperature for 15 minutes and a solution of trichloroacetyl chloride (60 ml, 0.535 mol) in dichloromethane (500 ml) was added dropwise maintaining temperature of the reaction mass below 0° C. The reaction mass was then stirred for 2-3 hours below 0° C. and quenched with water (500 ml) below 5° C. The organic phase was then separated and aqueous layer was reextracted with dichloromethane. The combined dichloromethane layer was washed with water, dried over sodium sulfate and evaporated under vacuum to obtain (72 g) of the desired product.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:24]([NH:26][C@@H:27]([C:32](O)=[O:33])[C@@H:28]([CH2:30][CH3:31])[CH3:29])=[O:25])[CH:13](CC1C=CC=CC=1)[C:14](=[O:16])[OH:15])=O)C1C=CC=CC=1.Cl.[CH3:36][O:37][CH2:38][C@H:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH3:36][O:37][CH2:38][C@H:39]([NH:46][C:32](=[O:33])[C@@H:27]([C@@H:28]([CH2:30][CH3:31])[CH3:29])[NH:26][C:24](=[O:25])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH2:11])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC[C@@H](C)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Reactant: COC[C@H](N)c1ccccc1
Agent: Cl
Product: CC[C@@H](C)[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(=O)N[C@@H](COC)c1ccccc1
Yield: 22.1 %

Procedure:
The same process as in Example 15 was repeated, except that N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine was used in place of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine and that (R)-α-methoxymethylbenzylamine hydrochloride was used in place of (R)-α-ethoxymethylbenzylamine hydrochloride, and α-L-aspartyl-D-isoleucine (R)-α-methoxymethylbenzylamide was obtained as a solid product. The total yield was 22.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:13]=1[NH2:25].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:18]([CH:19]([CH2:22][O:23][CH3:24])[CH2:20][CH3:21])[C:14]=2[N:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(C)=O
Reactant: CCC(COC)Nc1nccc(-c2ccc(OC(F)F)cc2Cl)c1N
Product: CCC(COC)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
4-(2-Chloro-4-difluoromethoxy-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine (0.268 g, 0.72 mmol) and methyl pyruvate (130 μL, 1.44 mmol) were treated substantially as described in Part F of Example 113 to give 8-(2-chloro-4-difluoromethoxy-phenyl)-4-(1-methoxymethyl-propyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 122a): 1H NMR (300 MHz, CDCl3) δ □8.54–8.51 (m, 1H), 7.33–7.32 (m,2H), 7.21–7.14 (m, 2H), 6.85–6.37 (t, 1H, J=72.9 Hz), 6.21–6.19, 5.64–5.58 (2m, 1H), 4.40–4.31 (m, 1H), 3.92–3.79 (m, 1H), 3.33 (s, 3H), 2.48 (s, 3H), 2.30–2.20 (m, 1H),2.13–1.96 (m, 1H), 0.90–0.85 (t, 3H, J=7.7 Hz). MS (AP) m/z 424.1 [(M+H)+, 100].
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([CH:12]=[CH:13][C:14]=2[OH:15])[C:8]([NH:10][CH3:11])=[O:9])[CH2:3][CH2:2]1.I[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:35]=[CH:34][C:25]2[CH2:26][CH2:27][CH:28]([C:30]([O:32][CH3:33])=[O:31])[O:29][C:24]=2[C:23]=1[CH2:36][CH:37]=[CH2:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([OH:16])=[C:7]([C:8]([NH:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=2[O:15][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:35]=[CH:34][C:25]3[CH2:26][CH2:27][CH:28]([C:30]([O:32][CH3:33])=[O:31])[O:29][C:24]=3[C:23]=2[CH2:36][CH2:37][CH3:38])[CH2:2][CH2:3]1
Reactant: CNC(=O)c1ccc(O)c(CC2CC2)c1O
Reactant: C=CCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 16 (50 mg, 0.226 mmol), methyl 3,4-dihydro-7-(3-iodopropoxy)-8-(2-propenyl)-2H-1-benzopyran-2-carboxylate (95 mg, 0.226 mmol), and potassium carbonate (78 mg, 0.565 mmol) were added to 10 ml of DMF, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and extracted with ethyl acetate then dried over magnesium sulfate and concentrated in vacuo to give the crude product. Chromatography of the crude product on silica gel using 15% ethyl acetate/85% hexane as eluant provided the product.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][C:12]#[C:13][CH2:14]Cl)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:16][C:17]1[N:25]=[C:24]([NH2:26])[N:23]=[C:22]2[C:18]=1[NH:19][CH:20]=[N:21]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:6]([O:5][P:4]([CH2:9][O:10][CH2:11][C:12]#[C:13][CH2:14][N:21]1[CH:20]=[N:19][C:18]2[C:22]1=[N:23][C:24]([NH2:26])=[N:25][C:17]=2[Cl:16])([O:3][CH2:1][CH3:2])=[O:8])[CH3:7]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOP(=O)(COCC#CCCl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COCC#CCn1cnc2c(Cl)nc(N)nc21)OCC
Temperature: 20 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
A mixture of (4-chloro-2-butynyloxy)methylphosphonic acid diethylester (2.03 g, 8 mmol), 6-chloro-2-aminopurine (2 g, 12 mmol) and potassium carbonate (1.85 g, 12 mmol) in anhydrous dimethylformamide (15 ml) is stirred 2 days at 20° C. under argon. The reaction mixture is concentrated in vacuo, and the residue is purified by flash chromatography on silica gel to give the title product (1.7 g, 65%).
Reaction SMILES: [NH2:1][CH3:2].[F:3][C:4]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:5]=1[CH2:6][O:7][CH2:8][C:9]#[C:10][CH2:11]Br>O1CCCC1>[CH3:2][NH:1][CH2:11][C:10]#[C:9][CH2:8][O:7][CH2:6][C:5]1[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:4]=1[F:3]
Reactant: CN
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Solvent: C1CCOC1
Product: CNCC#CCOCc1cc(Br)ccc1F
Yield: 83 %

Procedure:
A solution of aminomethane (89 ml of a 2 M solution in tetrahydrofuran, 178 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (6.0 g, 17.8 mmol) in tetrahydrofuran (89 ml). The cloudy reaction mixture was stirred for about fifteen minutes, at which time no starting material remained, as determined by thin layer chromatography. The solvents were removed in vacuo. The residue was taken up in methylene chloride and washed with 1 M potassium carbonate. The aqueous phase was back-extracted thrice with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by flash chromatography, affording 4.24 grams (83%) of the title intermediate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3S[CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:34]1N=CC=C[N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:31][CH3:32])[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]3[N:35]=[CH:34][CH:28]=[CH:29][N:30]=3)[CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Brc1ncccn1
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine but substituting 2-bromo pyrimidine provided the title compound as an amporphous solid: 1H NMR (400 MHz, CDCl3) δ) 8.38, 7.50, 7.32, 7.26, 6.56, 5.30, 4.91, 4.25, 3.94, 3.76, 3.55, 2.73, 2.47, 1.33–1.26, 1.16; HRMS (ESI) calcd for C24H28N6OCl2+H1 487.1780. found 487.1770.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7](=[S:9])[NH2:8].[CH2:10]([O:12][C:13](=[O:22])[CH:14](Cl)[C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13]([C:14]1[S:9][C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:15]=1[C:16]([F:17])([F:18])[F:19])=[O:22])[CH3:11]
Reactant: NC(=S)c1ncccn1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ncccn2)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 2-pyrimidinecarbothioamide (2 g) and 2-chloro-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (3.2 g) in 10 mL of DMF is heated at 110° C. with stirring overnight. The mixture is concentrated under vacuum, and purified on silica gel column to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([I:18])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5][N:6]([OH:9])[CH:7]=[O:8].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:14]([O:13][C:12]1[C:2]([NH:1][CH3:19])=[CH:3][C:4]([CH2:5][N:6]([OH:9])[CH:7]=[O:8])=[CH:10][C:11]=1[I:18])[CH2:15][CH2:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CCCCOc1c(N)cc(CN(O)C=O)cc1I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCOc1c(I)cc(CN(O)C=O)cc1NC
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
A mixture of N-(3-amino-4-butoxy-5-iodo-benzyl)-N-hydroxy-formamide (36 mg, 0.1 mmol), potassium carbonate (11 mg, 0.11 mmol) and iodomethane (9.2 ul, 0.15 mmol) in DMF (1 ml) was stirred 18 h at room temperature. The mixture was partitioned between ethyl acetate and water, the organic extract was washed with brine then dried with sodium sulfate and all voltiles removed. Purification by preparative HPLC afforded the title compound (8 mg, 22%) 1H NMR (400 MHz, CD3OD) δ 8.36* 7.16 (s, 1H), 7.00 (s, 1H), 6.59 (s, 1H), 4.58* 4.54 (s, 2H) 3.84 (t, j=6.2 Hz, 2H), 2.83* 2.81 (s, 3H) 1.83-1.87 (m, 2H), 1.54-1.59 (m, 2H), 1.03 (t, j=7.1 Hz, 3H). M+1=379.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].Cl[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=2[N:19]=1>>[F:1][C:2]1[C:7]([O:8][CH2:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COc1ccc2nc(CCl)sc2c1
Product: COc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2c1
Yield: 19 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and 2-(chloromethyl)-6-methoxy-1,3-benzothiazole according to Method B, scheme 2. Yield 19%, mp 190-192° C., HPLC-MS (method 1): m/z 351 [M+H]+, Rt=3.50 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20](Cl)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)CO.CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=4)=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25]([CH2:26][CH2:27]5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Reactant: Nc1ccc(O)cc1
Solvent: OCCO
Solvent: CS(C)=O
Product: Oc1ccc(Nc2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(Cc5ccccc5)CC4)c3n2)cc1
Yield: 28.4 %

Procedure:
50 mg (0.11 mmol) of 1-(1-benzylpiperidin-4-yl)-6-chloro-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine was dissolved in 1 mL ethylene glycol. 0.24 mmol (26.2 mg) 4-aminophenol was added and the mixture was heated under microwave irradiation to 220 C (15 min). The mixture was diluted with 1 mL DMSO and purified by HPLC (TFA buffers) to give 16 mg of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][C:25]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1)=[O:26]>CC(=O)CC.CN(C)C=O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][C:25]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=[O:26])[CH2:12][CH2:11]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C(CCCl)N1CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: O=C(CCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 50 °C

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine, hydrochloride (8.0 g) and potassium carbonate (15 g) in a mixture of butanone (50 mL) and dimethyl formamide (5 mL) was heated to 50° C. followed by the addition of 3-chloro-1-(2,3-dihydro-1H-indol-1-yl)propan-1-one (6.0 g). The resulting mixture was boiled under reflux for 40 h and filtered hot. The remaining organic phase was left to crystallise, and a white crystalline material was collected by filtration and washed with acetone (8.5 g). Mp 157–158° C. 1H NMR (DMSO-d6): 2.60 (s, 4H); 2.60–2.80 (m, 4H); 3.00 (s, 4H); 3.15 (t, 2H); 4.10 (t, 2H); 6.95 (t, 1H); 7.10–7–15 (m, 2H); 7.20 (d, 1H); 7.25–7.35 (m, 2H); 8.10 (d, 1H). MS m/z: 404 (MH+), 243.