Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[O:2].[CH:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=3[N:16]3[C:12](=[N:13][N:14]=[CH:15]3)[CH2:11][N:10]=2)=[CH:7][CH:8]=1>>[OH:2][CH2:1][C:15]1[N:16]2[C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:9]([C:6]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)=[N:10][CH2:11][C:12]2=[N:13][N:14]=1
Reactant: C=O
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Product: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 1.5 h

Procedure:
The TLC test indicated that the reaction was not yet complete so another 1 g of paraformaldehyde was added 45 minutes after the first. Heating of the reaction mixture was continued at 125° C. After 1.5 hours total heating, a second TLC sample was taken and analyzed as above and it indicated that the estazolam was almost all consumed. To ensure complete reaction, another 0.5 g of paraformaldehyde was added and heating of the mixture was continued at 125° C. for another 45 minutes (2.25 hours total heating time), at which time testing by TLC analysis indicated reaction was substantially complete to form 1-(hydroxymethyl)-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=O>C(COC)OC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([CH:13]3[CH2:15][CH2:14]3)[N:8]=2)[N:7]=1
Reactant: O=C(CBr)C1CC1
Reactant: Nc1ccc(Cl)nn1
Solvent: COCCOC
Product: Clc1ccc2nc(C3CC3)cn2n1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 6-chloropyridazin-3-amine x104 (24.63 g, 0.19 mol) and 2-bromo-1-cyclopropylethanone (31 g, 0.190 mol, 1 eq) in dimethoxyethane (400 ml) is refluxed under inert atmosphere for 2 days. After cooling to room temperature, the solvent is removed under reduced pressure, the crude is taken up in water (100 ml) and extracted with ethyl acetate (2×300 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure to furnish 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine x105 (Yield: 42%) which is used as such in the next step. Note that further title compound x105 can be extracted from aqueous layer after neutralization to pH 5 by addition of sodium hydroxyde, extraction with dichloromethane, drying (MgSO4), filtration and condensation under reduced pressure (additional 11.13 g are then collected).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.Cl>O1CCOCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(N)CO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of commercially available 2-amino-2-methyl-1-propanol (8.91 g, 100 mmol) in dioxane (20 mL) at 5° C. was added commercially available 3-bromobenzenesulfonyl chloride (2.88 mL, 20 mmol) and the mixture was vigorously stirred at 23° C. for 1 h. Poured into 1 N HCl, diluted with EtOAc, separated phases, washed organic layer with brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a white solid (5.47 g, 89%). MS (ISN) 306.1 [(M−H)−] and 308.2 [(M+2−H)−]; mp 138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15].Cl>N1C=CC=CC=1>[CH3:12][N:13]([CH3:18])[S:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)N(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of 8.5 g of methyl 4-aminobenzoate 13 and 43 ml of pyridine is added 12.1 g of dimethylsulfamoyl chloride, and the mixture is stirred at 50° C. for 2 hours. The reaction mixture to which is added ice-water is acidified with 6N hydrochloric acid and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is washed with ether-isopropyl ether to give 9.5 g (yield: 65.4%) of methyl 4-(dimethylaminosulfonyl)aminobenzoate 14.
Reaction SMILES: [CH2:1]([C:3]1([OH:17])[C:13]2[C:8](=[C:9]([O:14]C)[N:10]=[CH:11][CH:12]=2)[CH2:7][O:6][C:5](=[O:16])[CH2:4]1)[CH3:2]>Cl>[CH2:1]([C:3]1([OH:17])[C:13]2[CH:12]=[CH:11][NH:10][C:9](=[O:14])[C:8]=2[CH2:7][O:6][C:5](=[O:16])[CH2:4]1)[CH3:2]
Reactant: CCC1(O)CC(=O)OCc2c1ccnc2OC
Agent: Cl
Product: CCC1(O)CC(=O)OCc2c1cc[nH]c2=O
Reaction time: 8 h
Yield: 49.1 %

Procedure:
5-Ethyl-5-hydroxy-9-methoxy-4,5-dihydrooxepino[3,4-c]pyridin-3(1H)-one (0.5 g, 2.1 mmol) is heated under reflux for 9 hours in 1N hydrochloric acid (20 ml). The reaction mixture is concentrated under reduced pressure and the residue is again dried by the addition and evaporation of toluene twice, then left overnight under reduced pressure in the presence of phosphorus pentoxide. The resultant oil is dissolved in anhydrous acetonitrile (5 ml) and agitated under argon for 24 hours. The precipitate is filtered out and dried, which produces 0.23 g (49%) of a white solid (M), m.p. 118–119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([OH:21])=O)=[CH:12][N:11]3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.[C:30]1([C:36]([NH2:39])([CH3:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:21])[NH:39][C:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([CH3:38])[CH3:37])[CH:17]=4)=[CH:12][N:11]3[C:25]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:4][CH:3]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) and 2-phenylpropan-2-amine (21 mg, 0.15 mmol) were dissolved into DMF (0.7 mL) and TEA (0.1 mL). HATU (59 mg, 0.15 mmol) was added to this solution (solution became yellow). The reaction was stirred at rt for 2 hrs (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammonium acetate buffer) to yield 2-(4-fluorophenyl)-N-methyl-6-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)imidazo-[1,2-a]pyridine-3-carboxamide (24.1 mg, 0.045 mmol, 44% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 9.25 (br s, 1H), 8.14 (br s, 1H), 7.92-7.86 (m 3H), 7.81-7.79 (m, 3H), 7.63 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.35 (d, J=7.3 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 7.22 (t, J=7.2 Hz, 1H), 2.90 (s, 3H), 1.81 (s, 6H). LC-MS retention time 1.74 min; m/z 507 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 mM, and an analysis time of 5 min where solvent A was 10% acetonitrile/90% H2O/0.1% TFA and solvent B was 10% H2O/90% acetonitrile/0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:18][CH:19]2[CH2:29][CH2:28][C:22]3([CH2:27][CH2:26][N:25]([C:33](=[O:34])[CH2:32][C:30]#[N:31])[CH2:24][CH2:23]3)[CH2:21][CH2:20]2)=[N:5][C:6]([NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[NH:12][N:11]=2)=[N:7][CH:8]=1
Reactant: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CCC2(CCNCC2)CC1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC2(CCC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.9 %

Procedure:
To a solution of 5-chloro-N2-(5-cyclopropyl-1H-pyrazol-3-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine hydrochloride (270 mg, 0.6159 mmol) in a mixture of DCM and DMF (6 mL/2 mL) were added TEA (253.2 mg, 2.502 mmol), cyanoacetic acid (52.1 mg, 0.733 mmol), HOAT (124.8 mg, 0.9169 mmol) and EDCI (177.5 mg, 0.9259 mmol). The reaction mixture was stirred at rt for 1.5 h then quenched with water (30 mL), and extracted with DCM/MeOH (10/1, 80 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1). The crude product was recrystallized from MeOH (10 mL) to give the title compound as a white solid (106.6 mg, 36.91%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1>>[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]3[N:25]=[C:26]4[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]4)=[CH:22][CH:23]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: CCc1c(Cl)cccc1N1CCNCC1
Agent: Cl
Product: CCc1c(Cl)cccc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1

Procedure:
In a manner similar to that of other examples above, 1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 443.2 (Exact Mass: 442.21).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[N:17][CH:18]=2)[CH2:7]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([NH:34][O:33][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)=[O:22])=[N:17][CH:18]=2)[CH2:7]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(Cc3cccc(Cl)c3)C2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cnc(N[C@@H]2CCCN(Cc3cccc(Cl)c3)C2)cn1)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A mixture of (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (218 mg, 0.59 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (82 mg, 0.70 mmol), HOBt (103 mg, 0.76 mmol) and EDCI (146 mg, 0.76 mmol) in DMF (6 mL) was stirred at 0° C. for 1 hr and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between saturated sodium bicarbonate solution and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5) to give (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (251 mg, 91%) as an amorphous powder.
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[C:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:15]([N:13]2[CH2:12][C:11]3([N:8]([S:34]([C:31]4[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=4)(=[O:36])=[O:35])[CH2:9][CH2:10]3)[CH2:14]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCCCc1ccccc1)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(NCCCc1ccccc1)N1CC2(CCN2S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
In analogy to the experimental procedure of example 6b) 6-(3-phenyl-propylcarbamoyl)-1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate was converted using 4-chlorobenzene-1-sulfonyl chloride into the title compound which was obtained as a colorless sticky solid (25 mg, 17%). MS m/e: 434 (M+H)+.
Reaction SMILES: [N:1]1[NH:2][C:3]([NH:6][C:7]([C:9]2[C:14]([NH2:15])=[N:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11](Br)[N:10]=2)=[O:8])=[CH:4][CH:5]=1.[NH:21]([CH2:25]CO)[CH2:22]CO>CN(C=O)C>[N:1]1[NH:2][C:3]([NH:6][C:7]([C:9]2[C:14]([NH2:15])=[N:13][C:12]([C:16]([F:19])([F:18])[F:17])=[C:11]([N:21]([CH3:25])[CH3:22])[N:10]=2)=[O:8])=[CH:4][CH:5]=1
Reactant: OCCNCCO
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1ccn[nH]1
Solvent: CN(C)C=O
Product: CN(C)c1nc(C(=O)Nc2ccn[nH]2)c(N)nc1C(F)(F)F
Temperature: 100 °C

Procedure:
To a stirring solution of 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (2H-pyrazol-3-yl)-amide (Ex. 7)(50 mg, 0.142 mmol) in dry DMF (5 ml), diethanolamine (37.4 mg, 0.356 mmol) was added. The resulting solution was heated at 100° C. using microwave radiation for 66 hours. The reaction mixture was partitioned between EtOAc (20 ml) and water (20 ml), and the phases separated. The organic phase was washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo to give an orange solid. Purification of the crude product by chromatography on silica eluting with iso-hexane/EtOAc (gradient of 0 to 50% EtOAc) yielded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl.[N:32]1([CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([CH2:45][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[CH:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:43][CH:42]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: COc1cc(NCCCc2ccc(CCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 48.5 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (32 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[CH3:18][C:19]1[N:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:21][CH:20]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ccc(-c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1

Procedure:
The product of Example 1B (123 mg, 0.42 mmol) and 6-methylpyridine-3-boronic acid pinacol ester (111 mg, 0.51 mmol; Synthonix) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.01-2.17 (m, 4 H), 2.60 (s, 3 H), 3.03-3.14 (m, 3 H), 3.20-3.29 (m, 2 H), 4.27 (s, 2 H), 7.03-7.06 (m, 1 H), 7.10 (t, J=7.6 Hz, 1 H), 7.34 (dd, J=7.6, 1.2 Hz, 1 H), 7.42 (d, J=8.2 Hz, 1 H), 7.96 (dd, J=7.9, 2.4 Hz, 1 H), 8.63 (d, J=2.1 Hz, 1 H); MS (APCI) m/z 304 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:24]([O:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([CH:34]=O)[CH2:30][CH2:29]1)[CH2:25][CH3:26]>CCOCC>[CH3:2][O:3][CH:4]=[CH:34][C@H:31]1[CH2:30][CH2:29][C@H:28]([O:27][CH2:24][CH2:25][CH3:26])[CH2:33][CH2:32]1
Reactant: CCCO[C@H]1CC[C@H](C=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CCOCC
Product: CCCO[C@H]1CC[C@H](C=COC)CC1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 94.6 g. of (methoxymethyl)triphenylphosphonium chloride in 1000 ml. of dry ether is treated with 33.0 g. of potassium tert.butylate. After stirring for 45 minutes, a solution of 31.4 g. of trans-4-n-propyloxycyclohexane carboxaldehyde in 200 ml. of ether is added dropwise. The mixture is stirred for a further 2.5 hours and then poured into 1.2 liters of ice-water. The organic phase is separated, washed neutral with water, dried over sodium sulfate and evaporated. The crude trans-2-(4-n-propyloxycyclohexyl)vinyl methyl ether obtained is distilled at 82°-85° C./0.6 mmHg in order to separate the residual triphenylphosphine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1F)[CH:7]=[O:8])[CH3:2].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:13][CH2:14][CH3:15])[C:11]=1[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1cc(C=O)cc(OCC)c1-n1cncn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
5.00 g (23.6 mMol) of 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), 3.25 g (=2.0 eq.) of 1,2,4-triazole and 6.51 g (=2.0 eq.) of potassium carbonate was dissolved under argon in 50 mL of DMSO; the reaction mixture was stirred for 1 hour at 110° C. Then, it was cooled down to ambient temperature, poured into crashed ice and extracted twice with ethyl acetate. The organic phases were washed with water, dried over MgSO4, filtered and evaporated i.V. The crude product was purified by chromatography (silicagel, eluent:gradient of n-heptane/ethyl acetate) to yield 5.28 g of the title compound as colorless solid. MS: 261.9 (MH+).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:35][C:36]1[N:41]=[C:40](Cl)[CH:39]=[CH:38][N:37]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:38]5[CH:39]=[CH:40][N:41]=[C:36]([Cl:35])[N:37]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccnc(Cl)n4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Yield: 29.7 %

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (45.9 mg) in DMF (2 mL) was added diisopropylethylamine (73 μL) followed by 2,4-dichloropyrimidine (24.9 mg). The resulting solution was heated to 100° C. for 16 h then the mixture concentrated in vacuo. This crude was purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 18.3 mg of 2-((S)-1-phenylethylamino)-4-(5-(2-chloropyrimidin-4-yl)aminobenzimidazol-1-yl)pyrimidine (L-860,182). 1H NMR (500 MHz, CDCl3, partial): δ 8.51 (br s, 1H); 8.42 (d, J=5.5 Hz, 1H); 8.13 (d, J=5.9 Hz, 1H); 7.75 (s, 1H); 7.45 (d, J=7.3 Hz, 2H); 7.40 t, J=7.7 Hz, 2H); 6.77 (d, J=5.3 Hz, 1H); 6.56 (d, J=6.0 Hz, IH); 1.66 (d, J=6.9 Hz, 3H). Mass spectrum (ESI) 443.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15][N:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=4)[CH2:29][CH2:28]3)[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)c2nc(CCl)cn2c1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Fc1ccc(N2CCN(Cc3cn4cc(C(F)(F)F)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 2.25 h
Yield: 64.8 %

Procedure:
A mixture of 8-chloro-2-(chloromethyl)-6-trifluoromethylimidazo[1,2-α]pyridine (0.341 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.264 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 2.25 h at 80-85° C. After cooling, the mixture is partitioned between water and dichloromethane and the combined inorganic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) and the appropriate fractions combined, concentrated, and crystallized from ether/hexane to give 0.339 g of the title compound; mp 91-97° C.; MS m/z 412, 414; IR (mineral oil) 1322, 1161, 1153, 1512, 1171 cm-1 ; 1H NMR (CDCl3) δ2.76, 3.15, 3.87, 6.88, 6.96, 7.41, 7.75, 8.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:5]2.[C:18]1([NH:24][CH2:25][CH2:26][OH:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH2:14][C:15]([N:24]([CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])=[O:12])=[CH:5]2
Reactant: OCCNc1ccccc1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCC(=O)N(CCO)c1ccccc1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of N-[(5-chloro-1H-indol-2-yl)carbonyl]glycine (Cas Reg No 186429-62-9; Hulin, Bernard, et al, PCT International Patent Application (1996) WO 9639384; 374 mg, 1.5 mmol) and 2-(phenylamino)ethanol (228 mg, 1.6 mmol) in THF (20 ml) was stirred at ambient temperature for 30 minutes. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)4-methylmorpholinium chloride (DMTMM) (480 mg, 1.6 mmol) was added and the reaction mixture stirred at ambient temperature overnight, poured into water (15 ml) and extracted with ethyl acetate (3×15 ml). The organic extracts were combined and washed with 1N citric acid solution (15 ml), sodium bicarbonate solution (15 ml), dried over magnesium sulphate, filtered and concentrated to give the title product (471 mg, 86%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[NH:1]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:10]=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)Cc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2ncccc2[nH]1
Reaction time: 3 h
Yield: 96 %

Procedure:
18.4 g of ethyl 3-(3-nitropyridin-2-yl)-2-oxopropionate and 5.5 g of 10% palladium-on-charcoal are added to 500 ml of ethanol, and the reaction mixture is hydrogenated under 2 bar for 3 hours at 20° C. The reaction mixture is then filtered over a thin layer of silica gel and the filtrate is concentrated under reduced pressure, to give 14.1 g of ethyl 1H-pyrrolo[3,2-b]-pyridine-2-carboxylate, the characteristics of which are as follows: