Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]2[C:8]([O:10][C:11]3([C:21]4[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=4[O:19][C:13]4[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]3=4)[C:3]=2[CH:2]=1)=[O:9].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH:29]=[CH:28]1>C(O)(=O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C:8]([OH:10])=[O:9])=[C:3]([C:11]2[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=3[O:19][C:20]3[C:21]=2[CH:22]=[CH:23][C:24]([CH:25]=3)=[O:26])[CH:2]=1.[C:27]([OH:32])(=[O:33])/[CH:28]=[CH:29]\[C:30]([NH2:7])=[O:31]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Solvent: CC(=O)O
Product: NC(=O)/C=C\C(=O)O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 350 milligrams (0.001 mols) of 5-aminofluorescein and 300 milligrams (excess) of maleic anhydride were mixed in 5.0 milliliters of glacial acetic acid and the mixture was stirred at ambient temperature for 24 hours. The yellow product formed was filtered off and washed three times with diethyl ether. 420 Milligrams of fluorescein-maleamic acid was obtained. 1.R (KBR) showed bands at 2.55; 3.28; 3.38; 4.05; 5.85; 6.30; 6.52; 6.88; 6.90; 7.70; 8.34; 8.52; and 8.30μ.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[N:48]2[CH:49]=[CH:50][N:51]=[C:47]2[C:46]([CH3:52])=[CH:45][CH:44]=1>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:41][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:43]4[N:48]5[CH:49]=[CH:50][N:51]=[C:47]5[C:46]([CH3:52])=[CH:45][CH:44]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:40])[C:37]([NH2:39])=[O:38]
Reactant: Cc1ccc(Br)n2ccnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(C)(C)C(N)=O)CC4)cc3n2)n2ccnc12
Temperature: 150 °C
Yield: 60.5 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)-thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (205 mg, 0.30 mmol), 5-bromo-8-methylimidazo[1,2-a]pyridine (75 mg, 0.35 mmol), Pd(PPh3)4 (34 mg, 0.03 mmol) and copper(I) thiophene-2-carboxylate (11 mg, 0.06 mmol) in dioxane (3 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then the desired product was eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give a solid that was triturated in MeOH, filtered and dried at 60° C. under vacuum for 24 hours to give 201 as a white solid (97 mg, 62%). LCMS (Method G) RT 5.11 min; [M+H]+ 535. 1H NMR (400 MHz, CHCl3-d): δ 9.29 (s, 1 H); 7.93 (d, J=7.3 Hz, 1 H); 7.75 (s, 1 H); 7.37 (s, 1 H); 7.15 (d, J=7.3 Hz, 1 H); 7.13-6.96 (m, 1 H); 5.21 (s, 1 H); 4.06 (t, J=4.7 Hz, 4 H); 3.91 (t, J=4.7 Hz, 4 H); 3.86 (s, 2 H); 2.73 (s, 3 H); 2.62 (s, 8 H); 1.25 (s, 6 H)
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:19][C:4]=2[S:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1.C(O)(=O)C(O)=O.C([O-])(=O)C([O-])=O>O.O1CCOCC1.CC(C)=O>[NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)=[O:33])[C:5]2[CH:16]=[CH:17][C:18]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:19][C:4]=2[S:3]1
Reactant: N=c1sc2cc(OC(F)(F)F)ccc2n1CCSc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCS(=O)c1ccncc1
Yield: 59 %

Procedure:
The procedure is as in Example 8, starting with 2-imino-3-[2-(4-pyridylthio)ethyl]-6-trifluoromethoxybenzothiazoline (2 g) and meta-chloroperbenzoic acid (90 pure by weight) (0.68 g) dissolved in water (25 cc) and dioxane (25 cc). The reaction mixture is stirred for 12 hours at 25.C and then concentrated to dryness at 40.C under reduced pressure (20 mm Hg; 2.7 KPa) to remove the dioxane. The aqueous solution is taken to a pH of 12-13 with concentrated ammonia solution (l0N) and then extracted with dichloromethane (2×50 cc). The organic phase is dried over anhydrous magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oil thereby obtained is purified by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bars), with a mixture of ethyl acetate and methanol (90:10 by volume) as eluent. An oil is thereby isolated, which oil, when treated with oxalic acid (0.25 g) and acetone (5 cc), gives 2-imino-3-[2-(4-pyridylsulphinyl)ethyl]-6trifluoromethoxybenzothiazoline (0.9 g) directly in the form of an oxalate, m.p. 194° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:22])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[S:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: O=C(Cl)C1CCCC1
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2nc(NC(=O)C3CCCC3)sc2-c2ccncc2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a solution of [4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.62 mmol) and 4-dimethylaminopyridine (0.06 g, 0.49 mmol) in N,N-dimethylacetamide (5 mL) was added cyclopentanecarbonyl chloride (0.32 g, 2.42 mmol) and the mixture was stirred at 70° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.43 g, yield 66%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=1[C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(O)c(C(=O)Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Phenylacetic acid (7.39 g, 54.28 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (4.74 ml, 54.28 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-methoxyanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (9.63 g, 72.37 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as yellow liquid (4.3 g, 49% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.30(s,1H), 7.42(d, J=3.0 Hz, 1H), 7.33-7.21(m, 5H), 7.17(dd, J=9.0,3.1 Hz, 1H), 6.92(d, J=9.0 Hz, 1H), 4.43(s, 2H), 3.74(s, 3H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39]([CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:40])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:40])[CH:41]=[CH:42][C:43]1[CH:48]=[CH:47][C:46]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][C:28](=[O:33])[NH:29][S:30]5(=[O:31])=[O:32])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:45][CH:44]=1)[CH3:37]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CCOC(=O)C=Cc1ccc(B(O)O)cc1
Product: CCOC(=O)C=Cc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (200 mg, 0.34 mmol) was treated as described in general procedure G using 4-(2-ethoxycarbonyl-vinyl)phenyl boronic acid to provide 3-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-acrylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([NH2:14])=[O:13].[F:15]C(F)(F)C1C=CC=C2C=1C=CN2CC(N)=O>>[F:15][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: NC(=O)Cn1ccc2c(Cl)cccc21
Reactant: NC(=O)Cn1ccc2c(C(F)(F)F)cccc21
Product: NC(=O)Cn1ccc2c(F)cccc21

Procedure:
2-(4-chloro-1H-indol-1-yl)acetamide 2 (MS (LC-MS, MH+): 209/211)) and 2-[4-(trifluoromethyl)-1H-indol-1-yl]acetamide 2a can be synthesized according to the same method.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12](=[O:13])[NH:8][C:7]2[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.01 h
Yield: 95.1 %

Procedure:
To a solution of 4-isopropylaniline (3.02 g, 22.3 mmol) in DCM (40 mL) and pyridine (10 mL) was added 4-nitrophenyl chloroformate (4.09 g, 20.3 mmol) portionwise with stirring over ˜30 sec with brief ice-bath cooling. After stirring at rt for 1 h, the homogeneous solution was diluted with DCM (100 mL) and washed with 0.6 M HCl (1×250 mL), 0.025 M HCl (1×400 mL), water (1×100 mL), and 1 M NaHCO3 (1×100 mL). The organic layer was dried (Na2SO4) and concentrated to give the title compound as a light peach-colored solid (5.80 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 8.28 (m, 2H), 7.42-7.32 (m, 4H), 7.22 (m, 2H), 6.93 (br s, 1H), 2.90 (h, J=6.9 Hz, 1H), 1.24 (d, J=6.9 Hz, 6H). LC/MS (ESI): calcd mass 300.1, 601.3 (2MH)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:23])([C:18]3[N:19]=[N:20][NH:21][N:22]=3)[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:23])([C:18]3[N:22]=[N:21][N:20]([CH3:30])[N:19]=3)[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1nn[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1nnc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
To a solution of 5-cyclopropyl-N-[2-cyclopropyl-1-methyl-1-(2H-tetrazol-5-yl)ethyl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 150b, 100 mg, 0.244 mmol) in dry DMF (1.2 ml) was added potassium carbonate (43.8 mg, 0.317 mmol). The reaction mixture was stirred at room temperature for 10 minutes followed by addition of iodomethane (30.5 μl, 0.487 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with water and brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by preparative HPLC to yield the title compound (40 mg, 39%) and also a second by-product as the regioisomer (11 mg, 10.6%). MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[NH2:16].O.[NH2:20]N>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:20][N:16]=[CH:15][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(N)OC
Reactant: NN
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccn[nH]2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of 1-(4-nitrophenyl)ethanone (605.5 mmol) and bis(methyloxy)methanamine (726 mmol) in N,N-dimethylformamide (1000 mL) was stirred for 1 h at 80° C. The reaction was concentrated in vacuo, the residue was dissolved in ethanol (1000 mL) and treated with hydrazine monohydrate (1816 mmol). After the reaction stirred 2 h at 70° C. it was cooled to room temperature and poured into ice-water (2000 mL). Product precipitated out of solution, which was filtered, washed with water (4×500 mL) and dried to provide the title product as a yellow powder (98%). ESMS [M+H]+: 190.2
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:21])=[C:13]([CH3:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[C:13]([CH3:20])=[C:12]([CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: N#Cc1ccccn1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1C

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyridine and 2-amino-4,5-dimethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-2-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:15]3=[O:26])[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[OH:34][C@@H:29]1[CH2:30][CH2:31][CH2:32][CH2:33][C@H:28]1[NH:27][C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:15]3=[O:26])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CS(=O)c1nc2ccc(Cn3ccnc(N4CCOCC4)c3=O)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(N2CCOCC2)nccn1Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 130 °C
Reaction time: 16 h
Yield: 42.5 %

Procedure:
A mixture of 1-((2-(methylsulfinyl)benzo[d]thiazol-6-yl)methyl)-3-morpholino pyrazin-2(1H)-one (250 mg, 0.64 mmol), (1R,2R)-2-aminocyclohexanol (221 mg, 1.92 mmol) and DIEA (248 mg, 1.92 mmol) in DMA (6.6 mL) was stirred at 130° C. for 16 h. The reaction mixture was cooled to rt and poured into water (30 mL). The mixture extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 1-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one as a light yellow solid (120 mg, 26.5%). 1H NMR (300 MHz, DMSO-d6) δ 7.96 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.18-7.22 (m, 2H), 6.90 (d, J=4.8 Hz, 1H), 5.01 (s, 2H), 4.72 (d, J=5.1 Hz, 1H), 3.65 (s, 8H), 3.55-3.52 (m, 1H), 3.36-3.31 (m, 1H), 2.07-2.02 (m, 1H), 1.90-1.86 (m, 1H), 1.63-1.62 (m, 2H), 1.30-1.22 (m, 4H). LCMS (ESI) m/z 442 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][O:20][CH2:21][C:22]#[CH:23])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:29](=[O:31])=[O:30].C(O)(=O)C>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][O:20][CH2:21][C:22]#[C:23][C:29]([OH:31])=[O:30])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: C#CCOCc1c(C)nc2c(OCc3ccccc3)cccn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1nc2c(OCc3ccccc3)cccn2c1COCC#CC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.6 %

Procedure:
To a solution of 8-benzyloxy-3-(2-propynyloxymethyl)-2-methylimidazo[1,2-a]pyridine (1 g) in tetrahydrofuran (10 ml) was added dropwise 10% solution of n-butyllithium in n-hexane (2.09 ml) at -60° C. under a nitrogen atmosphere. After being stirred for 10 minutes the solution was treated with dry ice (1.4 g), allowed to warm to room temperature, and acidified with diluted acetic acid. The resulting precipitates were collected by filtration, washed with water, and recrystallized from methanol to give 8-benzyloxy-3-(3-carboxy-2-propynyloxymethyl)-2-methylimidazo[1,2-a]pyridine (0.67 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11](OC)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 71.8 %

Procedure:
A mixture of 3-(1-piperidinylmethyl)benzoic acid, methyl ester (17.56 g) and lithium aluminium hydride (2.58 g) in tetrahydrofuran (500 ml) was stirred at room temperature for 30 h and quenched with water. The solid was removed by filtration and the filtrate distilled to give the title compound as a colourless oil (11.1 g) b.p. 135° (10-1 mm). TLC silica; ether; Rf 0.2.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[OH:8][NH:9][CH:10]([CH2:35][CH2:36][CH2:37][C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:23][N:22]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]>O1CCCC1.C(O)=O>[OH:8][N:9]([CH:10]([CH2:11][S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]=[CH:23][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][N:26]=2)[CH2:19][CH2:20]1)(=[O:14])=[O:13])[CH2:35][CH2:36][CH2:37][C:38]1[N:39]=[CH:40][CH:41]=[CH:42][N:43]=1)[CH:5]=[O:7]
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(C#Cc3ccccn3)cn2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(C#Cc3ccccn3)cn2)CC1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
Formic acid (1.8 mL, 50 mmol) and acetic anhydride (0.5 mL, 5 mmol) were mixed together at 0° C. for 30 minutes, before being added to a solution 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(pyridin-2-ylethynyl)pyrimidine (190 mg, 0.37 mmol) in tetrahydrofuran (5 mL) and formic acid (1.8 mL) at 0° C. The reaction was allowed to reach room temperature and was stirred for 45 minutes. The reaction was then evaporated in vacuo, and azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH and heated to 45° C. for one hour. The solution was evaporated in vacuo, and the residue triturated with Et2O to give a white solid which was collected by filtration, washed with Et2O and dried in vacuo to give hydroxy {1-[({4-[5-(pyridin-2-ylethynyl)pyrimidin-2-yl]piperazin 1-yl}sulfonyl)methyl]-4-pyrimidin-2-ylbutyl}formamide as a white solid. (64 mg, 32%).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.O>ClCCl>[C:9]([O:13][C:14]([NH:16][CH2:17][C@H:18]([N:23]1[CH2:24][CH2:25][N:26]([S:4]([CH2:3][CH:2]([CH3:8])[CH3:1])(=[O:6])=[O:5])[CH2:27][CH2:28]1)[C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(=O)(=O)CC(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
479 mg (3.0 mmol) of 2-methylpropane-1-sulfonyl chloride are added to a solution of 800 mg (2.8 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared as described in example 23.1) and 775 μl (5.5 mmol) of triethylamine in 8 ml of dichloromethane, cooled beforehand to 0° C. The reaction medium is stirred at ambient temperature for 18 h and then water is added and the medium is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 5/5 heptane/ethyl acetate mixture. 785 mg (71%) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate are obtained in the form of a colorless oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])([O-:10])=[O:9]>ClCCCl.C(N(CC)CC)C>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[O:15])([O-:10])=[O:9]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C[Si](C)(C)CCOC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
H--2-Trimethylsilylethyl 3-nitrobenzoate may be prepared as follows: a solution of 41.8 g of 2- trimethylsilylethanol in 200 cm3 of 1,2-dichloroethane and 51 cm3 of triethylamine is added to a solution of 66.0 g of 3-nitrobenzoyl chloride in 1000 cm3 of 1,2-dichloroethane cooled to 5° C. The reaction mixture is stirred for 12 hours at a temperature in the vicinity of 25° C., then the insoluble product is separated by filtration and washed with 2 times 50 cm3 of 1,2-dichloroethane. The filtrate is concentrated to dryness under reduced pressure at 40° C. The oily residue obtained is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 76.9 g of 2-trimethylsilylethyl 3-nitrobenzoate are thus obtained in the form of an oil used as it is in subsequent syntheses.