Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH2:16][O:17][CH3:18])(C)(C)C.[ClH:20].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[C:11]([CH2:16][O:17][CH3:18])[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:20]
Reactant: COCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCc1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-2-methoxymethyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (3.051 g; 8.003 mmol) in DCM (60 ml) was added slowly 4N HCl in dioxane (40 ml; 160 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 2 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-2-methoxymethyl-imidazol-1-yl)-ethylamine was obtained as a pale beige solid (2.750 g; 100%; presence of 2 eq. of HCl). LC-MS: tR=0.21 min.; [M+H]+=282.24 g/mol.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH:42]=O)[CH:40]=2)[CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)[CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=Cc1ccc2c(c1)OCCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCCC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see example 5A(j)) (188 mg, 0.503 mmol) and triethylamine (0.175 ml, 1.256 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) at rt was stirred at rt for 15 min then 3,4-dihydro-2H-chromene-7-carbaldehyde (for a synthesis see WO2007067511 Example 19 (chromane-7-carbaldehyde)) (68 mg, 0.419 mmol) in chloroform (2 ml) was added dropwise at rt. The reaction mixture was stirred at rt for 1 h then sodium triacetoxyborohydride (444 mg, 2.096 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. LCMS showed a mixture of product, some residual aldehyde. Additional sodium triacetoxyborohydride (267 mg, 1.258 mmol) was added and the reaction stirred at rt for 6 h. The reaction was quenched with NaHCO3 (aq) (20 ml) and extracted with 20% MeOH/DCM (3×30 ml). The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed (0-50% MeOH/DCM) to deliver the free base of the title compound as a pale yellow clear oil (49 mg, 0.11 mmol, 26%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].BrC[C:20]1[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.Cl.[CH3:30]N(C)C=O>O>[C:26]([C:21]1[CH:20]=[CH:25][C:24]([CH2:30][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[C:3]2[N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:23][CH:22]=1)([OH:28])=[O:27]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccccc1CBr
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1c(-n2ccnc2)n(Cc2ccc(C(=O)O)cc2)c2ccccc12

Procedure:
A solution of 3-methyl-2-(1-imidazolyl)indole (1.50 g) in dimethylformamide (10 ml) is added dropwise to a suspension of 50% sodium hydride dispersion in mineral oil (0.77 g) in dimethylformamide (20 ml) stirred under nitrogen at 5°-10°. The suspension is stirred at 5°-10° for 1/2 hour. A solution of α-bromotoluic acid (1.63 g) in dimethylformamide (5 ml) is added dropwise to the suspension. The suspension is again stirred at 5°-10° for 1/2 hour and then overnight at room temperature. The suspension is diluted with water (100 ml) and acidified to pH 6 to 7 with 1N hydrochloric acid. The white precipitate which forms is collected by vacuum filtration, washed with water and dried to give 1-(p-carboxybenzyl)-2-(1-imidazolyl)-3-methylindole, m.p. 221°-5°. Recrystallization from acetonitrile gives crystals melting at 225°-7°.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li+].[BH4-]>C1COCC1>[C:1]12([CH2:11][NH:12][C:13]([C:15]3[N:20]4[CH:21]=[C:22]([CH2:24][OH:25])[N:23]=[C:19]4[CH:18]=[CH:17][CH:16]=3)=[O:14])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)c1cn2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccc2nc(CO)cn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 5-[(adamantan-1-ylmethyl)carbamoyl]imidazo[1,2-a]pyridine-2-carboxylate (7.0 g, 18.35 mmol) in THF (100 mL) at RT, is added portion-wise LiBH4 (799 mg, 36.7 mmol). The resulting mixture is stirred at RT for 16 h. The reaction is quenched by the slow addition of water, followed by the addition of EtOAc. The organic layer is separated, and the aqueous layer is back extracted with EtOAc. The combined organic layers are washed with water and brine, dried over sodium sulfate, and concentrated. The yellow solid is purified by re-crystallization from DCM to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:16]#[C:17][CH2:18][OH:19])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[NH2:21][N+:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCN2C(=NCCC2)CC1.O>CC#N>[CH2:1]([O:8][C:9]1[C:10]([C:16]2[C:17]([CH2:18][OH:19])=[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]3[N:21]=2)=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC#Cc1nc(Cl)ccc1OCc1ccccc1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: OCc1c(-c2nc(Cl)ccc2OCc2ccccc2)nn2ccccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
A mixture of compound 3-(3-(benzyloxy)-6-chloropyridin-2-yl)prop-2-yn-1-ol (1.9 g, 6.9 mmol), 1-aminopyridinium iodide (2.3 g, 10.4 mmol) and DBU (2.2 g, 14 mmol) in MeCN (15 mL) was stirred at 80° C. for 2 hours. Water (15 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (petroleum ether:ethyl acetate=1:1) to provide the product of compound (2-(3-(benzyloxy)-6-chloropyridin-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanol (1.2 g, yield: 47%). 1H-NMR (CDCl3, 400 MHz) δ 8.42 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.29˜7.22 (m, 3H), 7.21˜7.17 (m, 3H), 7.02 (t, J=8.0 Hz, 1H), 6.76 (dt, J=1.6, 8.0 Hz, 1H), 5.09 (s, 2H), 4.77 (d, J=6.4 Hz, 2H). MS (M+H)+: 366/368.
Reaction SMILES: [O:1]=O.[B].[CH2:4](B)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCC.[OH-].[Na+]>C(Cl)Cl>[CH2:4]([OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=O
Reactant: BCCCCCCCCCCCCC
Agent: [B]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCCO
Yield: 80 %

Procedure:
The kinetic product is a polyhomologated trialkylborane 6 (Scheme 1-6a). Following consumption of the salt, the reaction is exposed to the atmosphere during isolation of the product. During this time, organoborane 6 may be partially oxidized and hydrolyzed in basic aqueous solution to a mixture of boronic and boric acids/esters, and their hydroxy complexes. Although no formal oxidation-hydrolysis step was carried out after the polyhomologation reaction, the oxidation-hydrolysis was confirmed by both IR and NMR spectra, which indicate the existence of oxygen-carbon bonds and hydroxy groups in polymer 5. Solid state 11B NMR spectrum of polymer 5 also shows the characteristic signals for boronic and boric acids/esters, and their hydroxy complexes. The air oxidation of organoboranes is well-known. Furthermore, semicrystalline PE has good O2 permeability, which would facilitate air oxidation of the solid, boron-containing polymer. A model reaction with tridecylborane confirmed the spontaneous oxidation and hydrolysis. After stirring a DCM solution of tridecylborane with 50% NaOH solution in air, 80% of decanol was obtained. However, because the polymerization workup does not involve an exhaustive oxidation-hydrolysis, polymethylene 5 contains polymethylene boronic and boric acids/esters/complexes. These species can contribute to the relatively broad molecular weight distributions. If the as-synthesized polymethylene 5 is subjected to a formal oxidation-hydrolysis with trimethylamine N-oxide dihydrate in toluene at 80° C., all the boron species are fully oxidized and hydrolyzed. The resultant polymethylene product exhibits no boron signal on solid state 11B NMR spectrum, as shown in FIG. 11. Specifically, FIG. 11 shows a solid state 11B NMR spectra of as-synthesized polymethylene 5 (black) produced from trimethylsulfoxonium iodide 1 using trihexylborane as the initiator/catalyst in 50% NaOH aqueous solution/DCM mixture (Table 1-1, entry 1), and polymethylene (blue) produced after a formal oxidation-hydrolysis of polymethylene 5 with trimethylamine N-oxide dihydrate in toluene at 80° C. Trialkylboranes BR3 are typically in the range of 80-90 ppm, borinic acids/esters are in the range of 40-60 ppm, boronic acids/esters are in the range of 25-40 ppm, boric acids/esters are in the range of 10-25 ppm, tetracoordinated boron complexes are in the range of −10 to 10 ppm.
Reaction SMILES: [CH:1]1(CCCCCCCCCCCCN)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:25]([N:39]=[C:40]=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH:1]1([N:39]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:40]([NH:39][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:41])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: NCCCCCCCCCCCCC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCCCNC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 42, starting from 7.0 g of the compound of Example 1 and 4.8 g of tetradecyl isocyanate.
Reaction SMILES: [C:1]([CH:4]1[N:9](N=O)[CH2:8][C:7]2[S:12][CH:13]=[CH:14][C:6]=2[CH:5]1O)([OH:3])=[O:2].[OH-].[Na+]>C(O)C>[C:1]([C:4]1[CH:5]=[C:6]2[CH:14]=[CH:13][S:12][C:7]2=[CH:8][N:9]=1)([OH:3])=[O:2]
Reactant: O=NN1Cc2sccc2C(O)C1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2ccsc2cn1
Yield: 31.7 %

Procedure:
An initially homogeneous solution of 10 g (0.044 mole) of the nitroso derivative obtained in Example 1, 20 cc ethanol and 60 cc aqueous 20% sodium hydroxide is refluxed for 2 hours. After cooling and addition of ethanol, the resulting precipitate is filtered off, washed with ethanol and then with ether, after which it is dried. The resulting sodium salt (M.p.=260° C.; 4.7 g; 60%) is treated with 23 cc (1 equivalent) N hydrochloric acid. The material is found to dissolve at first and then to reprecipitate. It is directly recrystallized after addition of 27 cc water, to give 2.5 g (32%) pink crystals, M.p.=246° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38])[N:19]=[CH:18]3)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1ncc2cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1H-indazol-5-yl)pyridine-2(1H)-one (200 mg, 0.63 mmol) in DMSO (5 mL) was added Cs2CO3 (1.03 g, 3.15 mmol) and (3-bromopropoxy)-tert-butyldimethylsilane (0.15 mL, 0.66 mmol). After stirring overnight at ambient temperature under argon, the reaction mixture was filtered through a layer of Celite and concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one (90 mg, 29%). To a solution of 4-(benzyloxy)-1-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-indazol-5-yl)pyridin-2(1H)-one in THF (3 mL) was added TBAF (0.75 mL, 0.75 mmol, 1.0 M). After the reaction was complete, the mixture was treated with H2O, extracted with CH2Cl2, and the combined organics were concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes, 50:50) gave 4-(benzyloxy)-1-(1-(3-hydroxypropyl)-1H-indazol-5-yl)pyridin-2(1H)-one (50 mg, 88%) as a white solid. In accordance with the procedure of Example 1, the HCl salt was made to give the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.73-7.71 (m, 2H), 7.62 (d, J=7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.33 (dd, J=9.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.50 (t, J=7.0 Hz, 2H), 3.38 (t, J=6.5 Hz, 2H), 2.01-1.96 (m, 2H); ESI MS m/z 376 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1.Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:24][CH:25]=1)=[C:8]2[O:31][CH:32]([F:33])[F:34]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.56 g) in tetrahydrofuran (20 mL) was treated with 1.0 M aqueous lithium hydroxide solution (2.4 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with 0.1 M aqueous hydrochloric acid solution, concentrated under reduced pressure and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by trituration with a mixture of methanol and water, followed by column chromatography on C-18 column to afford title compound (0.35 g).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][NH:9][C@@H:8]([C@@H:10]([CH3:11])[CH2:12][CH3:13])[C:7]([O:6][C:2]([CH3:4])([CH3:5])[CH3:3])=[O:14])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CN[C@H](C(=O)OC(C)(C)C)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A solution of L-iso-leucine tert-butyl ester hydrochloride (5 g, 22.34 mmol) in DMF (30 mL) was treated with triethylamine (3.1 mL, 22.34 mmol), stirred for 1 hour at 25° C., filtered to remove solid salts, and the filtrate was treated with triethylamine (9.3 mL, 67.0 mmol) and ethyl bromoacetate (9.9 mL, 67.0 mmol), and the reaction was stirred for 3 hours at 25° C. The reaction mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (5.7 g, 93% yield), which was used without further purification.
Reaction SMILES: [CH:1]1([CH:4]2[N:9]=[C:8]([Cl:10])[C:7]([C:11]3[N:12](C(=O)C)[CH2:13][CH2:14][N:15]=3)=[C:6](Cl)[N:5]2[NH2:20])[CH2:3][CH2:2]1.[CH3:21][O-:22].[Na+]>CO>[Cl:10][C:8]1[C:7]([C:11]2[NH:12][CH2:13][CH2:14][N:15]=2)=[C:6]([O:22][CH3:21])[N:5]([NH2:20])[CH:4]([CH:1]2[CH2:2][CH2:3]2)[N:9]=1
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C2CC2)N=C1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1=C(C2=NCCN2)C(Cl)=NC(C2CC2)N1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
3.0 g 2-cyclopropyl-4,6-dichloro-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are mixed with a solution of 0.5 g sodium methylate in 30 ml methanol and stirred for three hours at room temperature. Then about 20 ml of methanol is distilled off. After adding water and extracting with chloroform, the organic phase is dried and concentrated. 1.9 g of 4-chloro-2-cyclopropyl-6-methoxy-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained; melting point 214° C. The hydrochloride obtained in known manner has a melting point of 200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:17]([C:35](O)=[O:36])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)=[O:22])[CH:17]([C:35]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:36])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Reactant: C1COCCN1
Product: O=C(C1CN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1)N1CCOCC1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine was reacted with morpholine to give 4-(6-bromonaphth-2-ylsulphonyl)-2-morpholinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 60% yield, m.p. 235-237° C.;
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1.[H-].[Na+].CO>CN(C=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (1.09 g, 6.2 mmol, 1 equiv) and 1-(bromomethyl)-4-bromobenzene (1.70 g, 6.82 mmol, 1.1 equiv) in anhydrous DMF (30 mL) under argon atmosphere was added sodium hydride (500 mg, 12.4 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then neutralized by addition of methanol and concentrated in vacuo. The residue was dissolved in AcOEt, washed with brine and dried over MgSO4. The crude was purified by flash chromatography (Hexane/AcOEt 7.5/2.5) to afford the title compound as a white powder (1.09 g, 3.2 mmol, 52%). ESI-MS (m/z): 344/346 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]([CH3:14])[N:20]=1)=[O:8])=[O:5]
Reactant: Cc1nc(N)ccc1-c1ccccc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)ccc1-c1ccccc1

Procedure:
2,6-Dichlorobenzoyl isocyanate (650 mg) was reacted with 6-methyl-5-phenyl-2-pyridylamine (500 mg) in 25 ml of ethyl acetate. A precipitate formed which was filtered and confirmed by NMR as the desired product, 219°-220° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13]O)[CH:6]=1>ClCCl>[ClH:3].[Cl:3][CH2:13][C:12]#[C:11][C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: OCC#Cc1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCC#Cc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 154.2 %

Procedure:
Thionyl chloride (11.9 g) was added dropwise to a solution of 3-(3-pyridyl)-2-propyn-1-ol (13.3 g) in dichloromethane (266 ml) at room temperature. After completion of the addition, the mixture was stirred for 2 hours at room temperature. The resulting precipitates were collected by filtration and washed with diethyl ether to give 1-chloro-3-(3-pyridyl)-2-propyne hydrochloride (14.5 g) as brownish crystals.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH2:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH3:7].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH2:6]([O:8][C:9]1[C:10]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][C:12]2[C:13]([CH3:21])([CH3:22])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1)[CH3:7]
Reactant: CCOc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(=O)CC)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Propionyl chloride (1.44 mL, 16.6 mmol) was added to a stirring solution of 3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (Intermediate 2, 3.5 g, 15.1 mmol) in dichloromethane (100 mL), and the solution was cooled to 0° C. Aluminum trichloride (2.21 g, 16.6 mmol) was added over two to three minutes, the ice-bath was removed, the yellow solution was stirred for 1 h at room temperature. The solution was poured over ice in a separatory funnel, and the products were extracted three times with ether. The combined organic layers were washed with 10% aqueous sodium hydroxide, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1>>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Clc1ccnc2ncccc12
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.304 mmol) was reacted with the product from Example 18b (83 mg, 0.304 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (29 mg, 24%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 6.34 (d, J=6.99 Hz, 1H), 7.17 (d, J=7.72 Hz, 1H), 7.23 (d, J=8.46 Hz, 2H), 7.28-7.34 (m, 2H), 7.49 (d, J=8.82 Hz, 2H), 7.90 (dd, J=8.46, 4.41 Hz, 1H), 8.48 (d, J=6.99 Hz, 1H), 9.11 (dd, J=8.46, 1.47 Hz, 1H), 9.17 (dd, J=4.41, 1.47 Hz, 1H), 10.04 (s, 1H), 11.12 (s, 1H); MS (ESI+) m/z 401 (M+H)+, (ESI−) m/z 399 (M−H)−.