Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:3].[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O>CO>[C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:14]([CH3:16])=[CH:13][C:12]([O:18][CH3:19])=[O:17])=[CH:7][CH:6]=1)(=[O:3])[CH3:1]
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)Nc1ccc(N)cc1
Solvent: CO
Product: COC(=O)C=C(C)Nc1ccc(NC(C)=O)cc1
Temperature: 5 °C
Yield: 46.8 %

Procedure:
A suspension of 4-aminoacetanilide (2) (253 g, 1.68 mol) and methyl acetoacetate (215 g, 1.85 mol) in MeOH (0.75 L) was heated to reflux. The resulting solution was held at reflux for 16 h and then cooled to 5° C. The resulting off-white precipitate was filtered and washed with MTBE (3×200 mL) to give butenoate 3 (195 g, 47% yield). The mother liquor was concentrated in vacuo and filtered to give a second crop of 3 as pale pink solids (141 g, 34% yield, 81% overall yield). 1H NMR (DMSO) δ 10.22 (s, 1H), 9.97 (s, 1H), 7.57 (d, 2H), 7.11 (d, 2H), 4.65 (s, 1H), 3.56 (s, 3H), 2.04 (s, 3H), 1.94 (s, 3H); 13C NMR (DMSO) δ 169.64, 168.07, 159.33, 136.48, 133.55, 124.52, 119.44, 84.47, 49.77, 23.81, 19.68.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]2[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].[F:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25](O)=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1>>[CH:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:15])[N:2]([NH:1][C:25](=[O:26])[CH2:24][C:19]3[CH:18]=[C:17]([F:16])[CH:22]=[C:21]([F:23])[CH:20]=3)[N:11]=2)[CH2:13][CH2:14]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(C2CC2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C2CC2)c2ccccc2c1=O

Procedure:
The product from Example 22B and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.94 (m, 2H) 0.93-1.09 (m, 2H) 2.42-2.55 (m, 1H) 3.73 (s, 2H) 6.95-7.29 (m, 3H) 7.92 (t, J=7.63 Hz, 1H) 7.98-8.13 (m, 1H) 8.32 (d, J=7.93 Hz, 2H) 11.56 (s, 1H); MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>N1C=CC=CC=1.O1CCOCC1.N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:8]2[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]2=[O:10])=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1cc([N+](=O)[O-])cn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
A mixture of methyl 5-nitro-2-oxo-1,2-dihydropyridine-3-carboxylate (850 mg, 4.29 mmol), 4-fluorophenylboronic acid (1.40 g, 10 mmol, Combi-Blocks) and copper acetate (200 mg, 1.1 mmol) in pyridine (1 mL) and dioxane (20 mL) was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with a solution of ammonia. The solid was collected, washed with water and dried to afford the title compound (656 mg, 52%). 1H NMR (DMSO-d6) δ 8.95 (d, 1H, J=3.2 Hz), 8.80 (d, 1H, J=3.2 Hz), 7.40 (m, 2H), 7.25 (m, 2H), 3.95 (s, 3H); MS(ESI+) m/z 293 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([NH:18][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nccc2[nH]cnc12
Reactant: NCc1ccccc1
Solvent: O
Product: c1ccc(CNc2nccc3[nH]cnc23)cc1

Procedure:
A mixture of 4-chloro-1H-imidazo-[4,5-c]-pyridine (2.0 g, 13 mmole), benzylamine (5 ml) and a few drops of water was heated at reflux for 4 days. The reaction mixture was poured onto ice and water and the cold mixture was extracted twice with diethylether. The ether was removed in vacuo and the residual oil was triturated twice with hexane. The oil was suspended in water and the aqueous phase was neutralised with glacial acetic acid. The aqueous phase was taken to dryness in vacuo and resuspended in water (15 ml). It was applied to a column of Dowex 50 (H+) (10 g). The column was washed with water until the ultra violet absorbance of the eluant had fallen to zero. The column packing was removed from the column and heated with several portions of concentrated ammonium hydroxide solution (400 ml). The basic solution was filtered in vacuo, cooled and neutralized with glacial acetic acid. The yellow solid was collected and dried in vacuo at 40° C. Yield of 4-benzylamino-1H-imidazo-[ 4,5-c]-pyridine 0.94 g, m.p. 60°-64° C., 31.5%.
Reaction SMILES: [NH2:1][C@@:2]1([C:12]([OH:14])=[O:13])[CH2:7][C:6](=[O:8])[C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10].N[C@]1(C(O)=O)C[C@H](F)[C@H]2[C@@H]1[C@@H]2C(O)=O.N[C@@]1(C(O)=O)CC(=C)[C@@H]2[C@H]1[C@H]2C(O)=O.N[C@H](C([O-])=O)CCC([O-])=O>>[NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:7][CH:6]([OH:8])[CH:5]2[CH:3]1[CH:4]2[C:9]([OH:11])=[O:10]
Reactant: N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: C=C1C[C@@](N)(C(=O)O)[C@H]2[C@@H]1[C@@H]2C(=O)O
Agent: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: N[C@]1(C(=O)O)C[C@H](F)[C@@H]2[C@@H](C(=O)O)[C@@H]21
Product: NC1(C(=O)O)CC(O)C2C(C(=O)O)C21

Procedure:
Particularly preferred compounds of formula I are (1S*,2S*,5R*,6R*)-2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (1S*,2S*,5R*,6R*)-2-amino-4-[anti]-hydroximinobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (1S*,2S*,5R*,6R*)-2-amino-4-[syn] -hydroximinobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid; (1S*,2R*,4S*,5S*,6S*)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; (1S*,2S-,5R*,6S*)-2-amino-4-Z-carboxymethylenebicyclo-[3.1.0]hexane-2,6-dicarboxylic acid and (1S*,2S*,5R*,6S*)-2-amino-4-methylenebicyclo[3.1.0]hexane-2,6-dicarboxylic acid. These compounds have been found to process especially high potency as metabotropic glutamate receptor modulators.
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH2:25]([O:32][C:33](=[O:50])[C@H:34]([CH3:49])[NH:35][C:36](=[O:48])[C@H:37]([CH3:47])[N:38]([C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH2:42])[CH3:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33](=[O:50])[C@H:34]([CH3:49])[NH:35][C:36](=[O:48])[C@H:37]([CH3:47])[N:38]([C:40](=[O:46])[C@H:41]([CH:43]([CH3:45])[CH3:44])[NH:42][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:17])[CH3:39])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 3.17 g (0.0537 mole) of Boc-N-methyl-L-leucine in 370 ml of dry dichloromethane was stirred and cooled at 0° C. as one-half of 13.15 g. (0.130 mole) of dry triethylamine was added, followed by 15.05 g (0.0591 mole) of BOP-CCl. This was stirred at 0° C. for 3 hours. The remainder of the triethylamine was added, followed by a solution of 13 g (0.0358 mole) of L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 50 ml of dry dichloromethane. The reaction was stirred at ice temperature for 22 hours, then washed with 125 ml of a 10% solution of potassium bisulfate. The organic layer was further washed with 2×100 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated to a small volume, and chromatographed on silica gel eluting with 1:1 ether/hexane gradually increasing the ether to 2:1. The product weighed 15.8 g (75% of theory), and the FAB m.s. showed a molecular ion peak at 591.
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O>[C].[Pd]>[OH:25][C:17]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(c2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Product: O=C(O)[C@@H]1CC(O)(c2ccccc2)CN1

Procedure:
A soluion of the N-carbobenzyloxy-4-hydroxy-4-phenyl-L-proline from part (a) is treated with a 5% palladium carbon catalyst and hydrogenated according to the procedure of Example 1(b) to yield 4-hydroxy-4-phenyl-L-proline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]2[CH2:13][C@H:12]([O:14][CH3:15])[CH2:11]2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C@H:10]2[CH2:11][C@H:12]([O:14][CH3:15])[CH2:13]2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: CO[C@H]1C[C@H](Nc2cc(F)ccc2N)C1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CO[C@H]1C[C@H](n2c([C@H](C)NC(=O)OC(C)(C)C)nc3ccc(F)cc32)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoro-N2(trans-3-methoxycyclobutyl)benzene-1,2-diamine (0.36 g, 1.7 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.35 g, 1.9 mmol) and HOAt (0.26 g, 1.9 mmol) in DCM (8 mL) was cooled to 0° C. under a nitrogen atmosphere. To this mixture was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.36 g, 1.9 mmol) portion wise and the mixture stirred at RT for 1 h. The reaction mixture was allowed to warm to RT then partitioned between DCM (30 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the compound as a pink solid (0.188 g, 29%). The compound thus obtained was dissolved in AcOH (8 mL) and heated at 70° C. for 18 h. After cooling to RT, the volatiles were evaporated in vacuo and the residue partitioned between DCM (40 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting dark brown residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as yellow oil (0.125 g, 20%). LCMS (Method B): RT 2.84 min [M+H]+ 364.05
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].OO.C[Si]([C:16]#[N:17])(C)C.CN(C)C(Cl)=O>C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:16]#[N:17])[CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccncc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: OO
Product: CCCc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To 4-propylpyridine (2.5 g, 20 mmol), 30% hydrogen peroxide (2.4 g) was added and refluxed overnight. The solvent was removed and the resulting residue was taken in DCM (30 mL). Trimethylsilyl cyanide (2.6 g, 26 mmol) was added to the above solution followed by dimethylcarbamyl chloride (2.8 g, 26 mmol), and the reaction mixture was stirred at rt overnight. Potassium carbonate (10%, 100 mL) was added. The organic layer was separated, dried over sodium sulfate and then concentrated to obtain 4-propyl-2-cyanopyridine (2.5 g, 93%). The crude nitrile was dissolved in aqueous hydrochloric acid (6N, 60 mL) and refluxed overnight. The 4-propyl-2-carboxylic acid pyridine 10b (R9=propyl) was obtained after crystallization from acetonitrile (2 g, 71%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].Cl.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1>O1CCCC1>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[O:30])[CH2:25][CH2:24]1
Reactant: NCC(=O)OCc1ccccc1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)NCC(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
4.2 cm3 of triethylamine and 3.02 g of benzyl glycinate hydrochloride are added, at 20° C., to 3 g of 4-methylpiperazin-1-ylcarbonyl chloride hydrochloride in solution in 150 cm3 of tetrahydrofuran. After stirring for 16 hours at 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in 70 cm3 of dichloromethane. The organic phase is successively washed with twice 100 cm3 of a saturated aqueous sodium bicarbonate solution and 70 cm3 of water, and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.9 g of benzyl N-(4-methylpiperazin-1-ylcarbonyl)-glycinate in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)O)=O)=[CH:5][CH:4]=1.[NH2:25][C:26]([NH2:28])=[S:27].O>CN(C)C=O>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:25][C:26](=[S:27])[NH:28][C:11]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: NC(N)=S
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of 4,4'-di(trifluoromethyl)benzoin (50 g, 0.15 mol) and thiourea (15.2 g, 0.2 mol) in dimethylformamide (350 ml) was refluxed under argon for three hours. The cooled solution was poured into 1 liter of water and the resulting solid was collected, washed with water, air-dried and recrystallized from ethanol to give 4,5-bis-(4-trifluoromethylphenyl)-1H-imidazole-2-thione, m.p. 312°-315°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16](O)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2ncc3c(Cl)ccnc32)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
1-(4-Methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (759 mg) was dissolved in phosphorus oxychloride (6 mL). The resulting mixture was stirred at 70° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and carefully washed with a sodium bicarbonate solution. The organic layer was dried (using sodium sulfate), and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate=5/0 to 3/1) to give 4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (568 mg, yield: 70%) as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:38])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13].[C:39]([OH:51])(=[O:50])[CH2:40][C:41]([CH2:46][C:47]([OH:49])=[O:48])([C:43]([OH:45])=[O:44])[OH:42]>C(O)C.CC(C)=O>[C:39]([OH:51])(=[O:50])[CH2:40][C:41]([CH2:46][C:47]([OH:49])=[O:48])([C:43]([OH:45])=[O:44])[OH:42].[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([F:38])=[C:18]([NH:20][C:21]([C:23]2[N:27]3[CH:28]=[CH:29][C:30]([C:32]4[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=4)=[CH:31][C:26]3=[N:25][CH:24]=2)=[O:22])[CH:19]=1)=[O:13]
Reactant: CC1CCCC(C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccnn4C)ccn23)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(C)=O
Solvent: CCO
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccnn4C)ccn23)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
7-(2-Methyl-2H-pyrazol-3-yl)-imidazo[1,2-a]pyridine-3-carboxylic acid {5-[2-(2,6-dimethyl-piperidin-1-yl)-ethylcarbamoyl]-2-fluoro-phenyl}-amide (step 3) (480 g) was suspended in ethanol (2300 mL) in a 5000 mL four-necked flask equipped with thermometer, reflux condenser and a nitrogen inlet. The mixture was heated to 55° C. and the suspension gradually became clear. A solution of citric acid (180 g) in acetone (2.4 L) was added over 1 h and the internal temperature was controlled at 45-50° C. The clear solution was stirred at 50° C. for 2 h. A crystal seed (1 g) was added to the reactor and the internal temperature was cooled to 20° C. at a speed of 8° C./h. The mixture was stirred at 20° C. for 60 h. The resulting solid was filtered and the filter cake was washed with acetone (1 L) and dried in vacuum (under 4 mbar at 55° C.) for 24 h to afford the title compound;
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=S)=[N:6][CH:7]=1.CI.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][CH3:14])=[NH:11])=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ccc(I)cn1
Reactant: COc1ccccc1CN
Solvent: CI
Solvent: CO
Product: COc1ccccc1CNC(=N)Nc1ccc(I)cn1
Temperature: 60 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
0.970 g (3.475 mmol) N-(5-iodopyridin-2-yl)thiourea was dissolved in 30 mL methanol, 0.30 mL (4.777 mmol) methyl iodide in 2 mL methanol was added dropwise, and the mixture was heated at 60° C. (oil bath temperature) for 20 min and subsequently stirred at room temperature for 18 hr. The solvent was removed under vacuum, and the intermediate product was redissolved in 30 mL ethanol. 1.50 mL (11.262 mmol) 2-methoxybenzylamine was added dropwise and heated for 1.5 hr at 85° C. (oil bath temperature). The solvent was then evaporated under vacuum. The crude product was redissolved in dichloromethane and extracted with water (2×50 mL). The organic phase was then extracted again with 2 N sodium hydroxide solution (1×50 mL) and washed with water (1×50 mL) to remove iodide salt from the product. After drying over magnesium sulfate and overlayering with pentane the product was crystallized. 1.252 g (3.080 mmol, 89%) N-(5-iodopyridin-2-yl)-N′-(2-methoxybenzyl)guanidine was obtained. For additional purification, a portion of the first crystallizate was again recrystallized from dichloromethane/water.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1.[C:29](O)(=[O:31])[CH3:30]>>[CH3:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)[C:8]2[CH:26]=[CH:27][O:28][C:7]=2[CH:6]=1
Reactant: CC(=O)O
Reactant: Cc1cc2occc2c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(C)cc4occc34)CC2)CC1

Procedure:
The title compound, white solid (101 mg, 88%), MS (ISP) m/z=385.4 [(M+H)+], mp 207.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate D) (136 mg, 0.3 mmol) and acetic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][OH:13])=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][N:8]=1.Cl[C:23]1[N:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.[H-].[Na+]>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:23]2[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[C:10](/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:9][N:8]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OCc1c(-c2ccccn2)noc1/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2c(-c3ccccn3)noc2/C=C/c2ccccc2)nc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of [3-pyridin-2-yl-5([E]-styryl)-isoxazol-4-yl]-methanol (1.5 g, 5 mmol) in DMF (30 mL) was added 6-chloro-3-pyridine-carbonitrile (0.82 g, 6 mmol) and sodium hydride (0.26 g of a 55% dispersion in mineral oil, 6 mmol). The mixture was stirred at 70° C. for 3 h. Then the temperature was raised to 90° C. for 1 h. After evaporation of the solvent the residue was partitioned (ethyl acetate/brine) and the organic phase was dried (Na2SO4) and filtered. Evaporation of the solvent followed by trituration with diisopropylether afforded the title compound (1.8 g, 88%) as a light brown solid. MS: m/e=381.3 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([Li])(C)(C)C.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]1[CH:3]=[N:4][NH:5][CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cn[nH]c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn[nH]c1
Temperature: 25 °C

Procedure:
To a solution of 4-iodopyrazole (0.964 g) in THF (20 mL) under nitrogen and cooled to -60° C. is added t-butyllithium (1.7M in pentane, 9 mL) at such a rate that the temperature remained below -55° C. Tributyltin chloride (1.2 mL) was then added and the mixture was allowed to warm to room temperature. The reaction was quenched with water, diluted with ethyl acetate, washed with water, dried (anhyd Na2SO4), filtered, and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 4-(tributylstannyl)pyrazole (0.288 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[Cl-].[CH2:39]([C:41]1[S:42][CH:43]=[C:44]([CH2:46][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:45]=1)[CH3:40].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:39]([C:41]1[S:42][CH:43]=[C:44](/[CH:46]=[CH:13]\[C:12]2[C:8]([O:7][CH2:6][C:5]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]4[N:27]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[S:29][C:30]=4[CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:9][N:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:11]=2)[N:45]=1)[CH3:40]
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(N4CCOCC4)sc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
A mixture of 3-({3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.75 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.89 g), potassium carbonate (0.29 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 4-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]morpholine as colorless crystals (0.25 g, yield 28%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 112-114° C.