Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][NH2:7].C[Al](C)C.C(N[C:23]([C:25]1[S:26][CH:27]=[CH:28][C:29]=1[NH:30][C:31]1[C:32]2[CH:39]=[CH:38][NH:37][C:33]=2[N:34]=[CH:35][N:36]=1)=[O:24])C1C=CC=CC=1.O>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][NH:7][C:23]([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[NH:30][C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[O:24])[CH:8]=[CH:9][CH:10]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=C(NCCc1cccc(F)c1)c1sccc1Nc1ncnc2[nH]ccc12
Reaction time: 0.25 h
Yield: 12.4 %

Procedure:
To a solution of 3-fluorophenethylamine (130 μL; 134 mg; 0.97 mmol) in anhydrous toluene (3 mL) placed in a microwave tube under nitrogen was added a solution of trimethylaluminum (390 μL; 2.00 M; 0.77 mmol) in toluene. The colorless solution was stirred at 25° C. for 15 min, before 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide (60 mg; 0.19 mmol), was added. The resulting green solution was stirred for 15 min under a flow of nitrogen, and microwaved to 120° C. for 30 min. The reaction mixture was allowed to cool down before water (0.1 mL) was added. The resulting beige suspension was stirred at 25° C. for 2 h, diluted with methanol and purified by chromatography on a SP1 Biotage system, using dichloromethane and methanol as eluents to afford 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid [2-(3-fluorophenyl)-ethyl]-amide (9 mg, 12%) as a white solid (HPLC: 98%, RT: 6.33 min). 1H NMR (DMSO-d6) 11.97 (br s, 1H), 11.37 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.33 (t, J=5.5 Hz, 1H), 7.75 (d, J=5.5 Hz, 1H), 7.37 (dd, J=3.7, 2.6 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.13-7.08 (m, 2H), 7.03 (td, J=8.1, 2.6 Hz, 1H), 6.45 (dd, J=3.7, 1.8 Hz, 1H), 3.53 (q, J=6.6 Hz, 2H), 2.90 (t, J=7.1 Hz, 2H); MS (m/z) 382 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]Br.[CH3:11][C:12]([CH3:17])([CH2:15][OH:16])[CH2:13][OH:14]>>[CH3:11][C:12]([CH3:17])([CH2:15][O:16][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)[CH2:13][OH:14]
Reactant: Fc1ccc(CBr)cc1Br
Reactant: CC(C)(CO)CO
Product: CC(C)(CO)COCc1ccc(F)c(Br)c1

Procedure:
This compound was prepared from 3-bromo-4-fluorobenzyl bromide and 2,2-dimethylpropan-1,3-diol using the method of Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH2:33][CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH2:33][CH2:34][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1C(=O)c2ccccc2C1=O
Reaction time: 0.33 h

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.00 g, 3.65 mmol) and 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanal (0.929 g, 4.57 mmol) under nitrogen in glacial acetic acid (10 mL) was treated with sodium triacetoxyborohydride (1.55 g, 7.31 mmol) at ambient temperature. After stirring for 20 min., the reaction was evaporated in vacuo and the residue was partitioned between EtOAc and 5% w/v aq. K2CO3. After separating the layers, the aqueous phase was diluted with sat. aq. NaCl and back-extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl, dried over MgSO4, filtered and evaporated in vacuo. The residue was dissolved in warm Et2O leaving a small residue of insolubles. The Et2O was decanted and evaporated to approximately half volume where precipitation occurred. The product was collected by filtration and dried under high vacuum: 1H NMR (d6-DMSO) δ 7.78-7.86 (4H, m), 7.73 (1H, s), 7.65 (1H, t, J=7 Hz), 7.25-7.30 (2H, m), 7.06-7.12 (3H, m), 4.18 (2H, q, J=7 Hz), 3.90 (2H, s), 3.65 (2H, t, J=6 Hz), 3.24 (2H, q, J=5 Hz), 1.80-1.89 (2H, m), 1.24 (3H, t, 7 Hz); ES+ MS: 462 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)[CH3:52]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:56]6[CH2:57][CH2:58][N:53]([CH2:51][CH3:52])[CH2:54][CH2:55]6)=[O:35])=[CH:32][C:31]=5[F:39])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=O)c2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(F)c2)CC1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (65.6 mg, 0.0968 mmol) obtained in Step A in Example 1-D-21 and N-ethylpiperazine (24.6 μl, 0.194 mmol) instead of 1-pyridin-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, and a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-3-fluoro-phenyl}-(4-ethyl-piperazin-1-yl)-methanone was obtained as a yellow solid (64.2 mg). Then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-138) as a yellow powder (39.2 mg, 76%).
Reaction SMILES: [CH2:1]1[O:24][C:4]2([CH2:21][CH2:20][C@@:19]3([CH3:22])[C:6](=[CH:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH2:11][CH2:12][C:13]3=[O:23])[CH2:5]2)[O:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.CCOCC>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.C(#N)C>[CH2:2]1[O:3][C:4]2([CH2:21][CH2:20][C@@:19]3([CH3:22])[C:6](=[CH:7][CH2:8][C@@H:9]4[C@@H:18]3[CH2:17][CH2:16][C@@:14]3([CH3:15])[C@H:10]4[CH:11]=[CH:12][C:13]3=[O:23])[CH2:5]2)[O:24][CH2:1]1
Reactant: C[C@]12CCC3(CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)OCCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@]12CCC3(CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12)OCCO3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
Under argon atmosphere, a solution of 5-androsten-3,17-dione 3-ethyleneketal 10 (4.95 g, 0.0150 mol) in anhydrous THF (150 mL) was cooled at 0° C. and treated with 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (18 mL, 0.018 mol). The solution was stirred 20 min at room temperature, cooled at −78° C., and treated with chlorotrimethylsilane (2.24 mL, 0.0176 mol). The reaction was allowed to warm to room temperature, then evaporated. The residue was diluted with dichloromethane, washed two times with water and brine, dried over magnesium sulfate, filtered, and evaporated. A solution of the crude silylenol ether in a dichloromethane-acetonitrile 2-5 (140 mL) was treated with palladium acetate (4.04 g 0.0180 mol) and refluxed for 30 min. The reaction mixture was cooled to room temperature and evaporated. The black residue was purified by flash chromatography (hexanes-ethyl acetate 4-1) to provide the enone 44 (3.49 g, 71%): 1H NMR (300 MHz, CDCl3) δ 1.085 (s, 3H), 1.09 (s, 3H), 1.21-1.93 (m, 11H), 2.15 (dd, J=2.7 and J=14.1 Hz, 1H), 2.26-2.34 (m, 2H), 2.58 (d, J=14.1 Hz, 1H), 3.95 (m, 4H), 5.40 (d, J=5.1 Hz, 1H), 6.04 (dd, J=3.2 and J=6 Hz, 1H), 7.50 (d, J=5.8 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-c2ccsc2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccsc2)cc1C(=O)O
Reaction time: 8 h

Procedure:
Methyl 2-Methoxy-5-(thiophene-3-yl)benzoate (124 mg) was dissolved in a solvent mixture of tetrahydrofuran/methanol/water (2/1/1, 3 ml). Lithium hydroxide (53 mg) was added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the residue was added to 3 N hydrochloric acid. The white solid thus precipitated was taken by the filtration as the title compound.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:21])OC(C)(C)C)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:8])[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.ClCCl.C1C=NC2N(O)N=NC=2C=1.[O:42]1[C:46]2([CH2:51][CH2:50][CH:49](C(O)=O)[CH2:48][CH2:47]2)[O:45][CH2:44][CH2:43]1.CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C=O)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]([NH:14][C:15]([CH:49]2[CH2:50][CH2:51][C:46]3([O:45][CH2:44][CH2:43][O:42]3)[CH2:47][CH2:48]2)=[O:21])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(C#N)CC1
Reactant: O=C(O)C1CCC2(CC1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)C1CCC2(CC1)OCCO2)C(=O)NC1(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from example 34, tert-butyl [(S)-1-(1-cyanocyclopropylcarbamoyl)-3-methylbutyl]carbamate, (1.1 g, 3.72 mmol) was admixed with 20 ml of 1:1 TFA/dichloromethane and stirred at RT for 30 min. Subsequently, the mixture was concentrated by evaporation under reduced pressure and taken up again in dichloromethane and toluene, and solvent and TFA residues were removed under reduced pressure. The resulting N-terminally protected product was reacted further directly. 283 mg (1.5 mmol) thereof were admixed at 0° C. with 136 mg of HOAt (1 mmol, 0.67 eq.), 195 mg of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid from example 33 (1 mmol, 0.67 eq.), 268 mg of EDCl (1.4 mmol, 0.93 eq.) and 0.32 ml of NEM (2.5 mmol) in 2.5 ml of THF and 0.25 ml of DMF, and the mixture was stirred at 0° C. to RT overnight. Subsequently, the solvent was distilled off under reduced pressure, and the residue was taken up in ethyl acetate and extracted by shaking with saturated sodium hydrogencarbonate solution and saturated NaCl solution. Drying over sodium sulfate and evaporating-off the solvent were followed by purification using RP-HPLC (gradient: acetonitrile/water and addition of 0.05% TFA). The product fractions were combined and freeze-dried. Yield: 25 mg (without mixed fractions), corresponds to 7% of theory. 1H NMR: 8.81 (s, 1H); 7.84 (d, 1H); 4.20 (m, 1H); 3.83 (s, 4H); 2.22 (m, 1H); 1.75-0.8 (3 m, about 13H, 1.05 (m, 2H); 0.82 (dd, 6H); MS (ESI+): 364.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Br)[CH:11]=[CH2:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)C>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: C=CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
3-Hydroxybenzaldehyde (1.00 g, 8.19 mmol) and allyl bromide (0.780 mL, 9.01 mmol) in N,N-dimethylacetamide (35 mL) was treated with Cs2CO3 (4.01 g, 12.3 mmol) and allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with diethyl ether (150 mL), washed with 1N HCl, saturated NaHCO3, brine, dried (MgSO4), filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica gel, using 7% ethyl acetate/hexanes as eluent) to provide the title compound as a clear oil (1.19 g, 89%).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:31]([CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:48]>C1COCC1.CCOCC.[Pd]>[ClH:48].[ClH:48].[CH3:7][N:8]([CH3:30])[CH2:9][CH2:10][CH:44]1[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][CH2:38][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:42][CH2:43]1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCN(CCCOc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCC1CCN(CCCOc2ccccc2)CC1

Procedure:
In a similar manner to Example 28, n-butyllithium (25.2 ml, 2.5M solution in hexanes) was added to a suspension of (2-dimethylaminoethyl)triphenylphosphonium bromide (28.7 g) in dry THF (200 ml). This mixture was then treated with a solution of 1-(3-phenoxypropyl)-4-piperidone (14.7 g) in THF (20 ml). The oil obtained after work up (6.24 g) was hydrogenated in IMS at 1 atmosphere over 10% palladium charcoal over 16 hours. The catalyst was removed by filtration. The filtrate was evaporated and the residue was dissolved in petroleum ether, b.p. 60°-80° C. The solution was dried and evaporated to give an oil which was dissolved in ether and acidified with ethereal hydrogen chloride to yield a precipitate. The precipitate was collected by filtration and recrystallised from IMS to give 4-(2-dimethylaminoethyl)-1-(3-phenoxypropyl)piperidine dihydrochloride, m.p. 294°-295° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:28])=O>C1COCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:28])=[O:6]
Reactant: COc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1c(OC2CCN(C(=O)OC(C)(C)C)CC2)cccc1C(=O)Cl
Reaction time: 4 h

Procedure:
To a solution of 2-methoxy-(N-t-butyloxycarbonyl-4-piperidyloxy)benzoic acid (3.2 g; 9.1 mmol) from Step 3 of Example 25 in THF was added thionyl chloride (1 mL; 13.7 mmol) and pyridine (2 drops) while under a nitrogen atmosphere. The solution was stirred for 4 hours and then concentrated under reduced pressure to dryness. The residue was suspended in ether and filtered, and the filtrate was concentrated to dryness to yield 2-methoxy-(N-t-butyloxycarbonyl-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:15][C:16]#[N:17])=[CH:9][NH:10]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1.C(OCC)C>C(O)C.C(Cl)Cl>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](/[C:15](=[CH:24]/[C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)/[C:16]#[N:17])=[CH:9][NH:10]2
Reactant: COc1cccc2[nH]cc(CC#N)c12
Reactant: O=Cc1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc2[nH]cc(/C(C#N)=C/c3cccnc3)c12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of sodium methanolate (261 mg, 4.8 mmol, 1.5 eq.) in anhydrous ethanol (40 mL) were added, under an argon atmosphere, of (4-methoxy-1H-indol-3-yl)-acetonitrile (600 mg, 3.2 mmol, 1.0 eq.) and, after 30 minutes stirring, pyridine-3-carbaldehyde (908 μL, 9.7 mmol, 3.0 eq.). The reaction apparatus was protected from light and the mixture heated at 60° C. Several amounts of sodium methanolate (4×1.0 eq.) and pyridine-3-carbaldehyde (4×1.0 eq.) were added after stirring for 24, 48, 72 and 96 hours respectively. The reaction was pursued for 2 days (6 days overall) at 60° C. and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98:2 to 97:3) to afford, after trituration with diethyl ether, the compound (27) as a yellow powder (510 mg, 58%). TLC: Rf=0.30 (CH2Cl2 96/EtOH, 4); mp: 177° C.; 1H NMR (DMSO, 500 MHz): δ (ppm): 3.90 (3H, s, 4′-methoxy), 6.66 (1H, d, J5′-6′=7.9 Hz, H5′), 7.07 (1H, d, J7′-6′=7.9 Hz, H7′), 7.14 (1H, t, J6′-5′=J6′-7′=7.9 Hz, H6′), 7.55 (1H, dd, J5″-4″=7.9 Hz, J5″-6″=4.9 Hz, H5″), 7.62 (1H, s, H2′), 7.78 (1H, s, H3), 8.31 (1H, d, J4″-5″=7.9 Hz, H4″), 8.59 (1H, d, J6″-5″=4.9 Hz, H6″), 8.91 (1H, s, H2″), 11.67 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.6 (4′-methoxy), 101.4 (C5′), 106.0 (C7′), 108.6 (C2), 111.9 (C3′), 114.7 (C3a′), 119.1 (C1), 124.1 (C5″), 124.3 (C6′), 126.6 (C2′), 131.1 (C3″), 134.9 (C4″), 138.0 (C3), 139.0 (C7a′), 150.3 (C6″), 150.4 (C2″), 153.7 (C4′); ESI-MS: m/z 276.1 ([M+H]+), 298.1 ([M+Na]+); HRESI-MS: m/z 276.1137 (calcd for C17H14N3O, 276.1137).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC3C=CC(C(O)=O)=CC=3)N=2)C=CC=1OC>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]4)[C:18](=[O:25])[N:17]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(Cc3ccc(C(=O)O)cc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 4 and 4-chloromethylbenzoic acid as described for compound 83. Crystallized from ethyl acetate. M.p. 189°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([O:22]S(C)(=O)=O)[C:17]=2[N:27]=1.[ClH:28]>>[ClH:28].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[N:27]=[C:17]2[C:18](=[O:22])[NH:19][CH2:20][CH:21]=[C:16]2[N:15]=1
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2c(OS(C)(=O)=O)nccc2[nH]1
Agent: Cl
Product: COc1cc(OS(C)(=O)=O)ccc1C1=NC2=CCNC(=O)C2=N1
Temperature: 25 °C

Procedure:
0.65 g of 2-(2-methoxy-4-methanesulfonyloxy-phenyl)-4-methanesulfonyloxy-imidazo [4,5-c]pyridine was dissolved in 35 ml of ethanolic hydrochloric acid, and the solution was stirred for an hour at room temperature. The precipitate which had formed was suction-filtered off and washed with ethanol. Yield: 0.53 g (91% of theory). Melting point: 193°-195° C. (decomp.).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:35]=[N:34][N:33]([CH2:36][C:37]2[O:38][CH:39]=[C:40]([C:42](=[O:44])[CH3:43])[N:41]=2)[N:32]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.O>[C:42]([C:40]1[N:41]=[C:37]([CH2:36][N:33]2[N:32]=[C:31]([NH:30][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:35]=[N:34]2)[O:38][CH:39]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)c1coc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: N#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990) (1.38 g, 6.33 mmol) in dry toluene (63 mL) was treated with DMF (0.02 mL, 0.3 mmol) followed by oxalyl chloride (0.84 mL, 9.50 mmol) and the reaction mixture was stirred at rt for 50 min. The solvent was then removed under reduced pressure. The resulting acid chloride was dissolved in CH2Cl2 (23 mL) and added dropwise to a solution of 1-(2-((4-amino-2H-1,2,3-triazol-2-yl)methyl)oxazol-4-yl)ethanone (WO 2009/077990) (1.31 g, 6.33 mmol) and DIPEA (3.3 mL, 18.99 mmol) in CH2Cl2 (40 mL) and the resulting mixture was stirred at rt overnight. Water was added, the layers were separated, and the aq. layer was extracted three times with CH2Cl2. The combined org. layers were washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound which was re-crystallized from hot EtOH to give a white solid: TLC: rf (4:6 hept-EA)=0.35. LC-MS-conditions 02: tR=0.99 min, [M+H]+=407.22.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.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>[Br:8][C:6]1[CH:5]=[C:4]([C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:3]=[C:2]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cc(Br)cc(-c2nc3ccccc3s2)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: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc(-c2cccnc2)cc(-c2nc3ccccc3s2)c1

Procedure:
4.74 g (12.8 mmol) of 2-(3,5-dibromophenyl)benzo[d]thiazole) according to Synthesis Example 5, 1.89 g (15.4 mmol) of pyridine-3-boronic acid, 0.44 g (3 mol %) of tetrakis(triphenylphosphine)palladium (0), and 5.31 g (38.4 mmol) of potassium carbonate were dissolved in 50 ml of tetrahydrofuran/H2O mixed in a volume ratio of 4/1. The solution was reacted at 80° C. for 12 hours. The acquired reactant was extracted with ethyl acetate and treated under reduced pressure to remove the solvent. The extract was separated through a column and dried, obtaining 2.54 g (Y=54%) of a white solid.
Reaction SMILES: C1COCC1.Cl[C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19].C(Cl)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:17]([NH:20][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1)[CH2:18][CH3:19]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CCCN
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O=C(Cl)c1ccccc1
Product: CCCNc1nc(SC)ncc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 40 mL of THF, 4-chloro-5-cyano-2-methylthiopyrimidine [Compound (V)] (1.86 g, 10.0 mmol) obtained in Reference Example 4 was dissolved, then n-propylamine (709 mg, 12.0 mmol) and morpholinomethylpolystyrene (7.0 g) were added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, chloroform (100 mL) and benzoylchloride polymer bound [about 2.5 mmol/g, 4.6 g, Canadian Journal of Chemistry, Vol. 55, p. 3351 (1977)] were added thereto, followed by further stirring at room temperature for 12 hours. After resins in the reaction mixture were filtered out, the filtrate was concentrated under reduced pressure to give 4-n-propylamino-5-cyano-2-methylthiopyrimidine [Compound (W) in which R1 represents n-propylamino].