Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([OH:27])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[C:29]1([C:35]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:43][CH2:42][C@@H:41]([F:44])[C@@H:40]3[C@H:36]2[CH2:37][NH:38][CH2:39]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.C(N(CC)CC)C>[C:45]1([C:35]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:43][CH2:42][C@@H:41]([F:44])[C@@H:40]3[C@H:36]2[CH2:37][N:38]([C:25](=[O:27])[CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:39]3)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1N1CCCC1)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h

Procedure:
0.28 cm3 of triethylamine and 0.32 g of carbonyldiimidazole are added to a solution, cooled to 4° C., of 0.57 g of the hydrobromide salt of (2-pyrrolidinophenyl)acetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.67 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in 20 cm3 of dry dichloromethane and 0.28 cm3 of triethylamine, is added. The reaction mixture is stirred at room temperature for 24 hours and then diluted with 100 cm3 of dichloromethane, washed twice with 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.5 cm, height 38 cm), eluting under a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting fractions of 20 cm3. Fractions 26 to 54 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from an acetonitrile and diisopropyl oxide mixture (25/75 by volume). 0.16 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[(2-pyrrolidinophenyl)acetyl]perhydroisoindole is obtained in the form of white crystals; melting point 170° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4](C(=O)C)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].N1CCOCC1.[S].Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[C:3]([OH:13])=[C:4]([CH2:23][C:22]([OH:25])=[O:24])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CC(=O)O
Reactant: CC(=O)c1cc(F)c(F)c(F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [S]
Solvent: O
Solvent: C1COCCN1
Product: O=C(O)Cc1cc(F)c(F)c(F)c1O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(3,4,5-trifluoro-2-hydroxyphenyl)ethanone (7.5 g), p-toluenesulfonic acid monohydrate (0.375 g), morpholine (10 mL) and sulfur (2.0 g) was stirred at 120° C. for 5 hr, and allowed to cool to room temperature, and hydrochloric acid (20 mL) and acetic acid (20 mL) were added to the reaction mixture. The reaction mixture was stirred at 100° C. for 3 hr, allowed to cool to room temperature, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:12][O:11][C:10]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:13][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cc(C=O)cc(O)c1OC
Product: CCOC(=O)CCCOc1cc(C=O)cc(OC)c1OC

Procedure:
Employing the method of Preparation 3, 3.30 g (18.41 mmol) of 3,4-dimethoxy-5-hydroxybenzaldehyde is alkylated with ethyl 4-bromobutyrate. 4-(2,3-Dimethoxy-5-formylphenoxy)butanoic acid, ethyl ester is obtained as a yellow-orange oil after drying under high vacuum at 60°0 C. (5.45 g, 100%): IR (neat) 1735, 1690 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 297 (M+ +H). Analysis calculated for C15H20O6 : C, 60.80; H, 6.80; O, 32.40. Found: C, 60.51; H, 6.86; O, 32.63.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]1([B-](F)(F)F)[CH2:11][CH2:10]1.[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:9]1([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH2:10]1
Reactant: Fc1ncccc1I
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ncccc1C1CC1
Temperature: 130 °C
Yield: 108.8 %

Procedure:
2-Fluoro-3-iodopyridine (300 mg, 1.34 mmol), potassium cyclopropyltrifluoroborate (498 mg, 3.36 mmol), palladium (II) acetate (30 mg, 0.135 mmol) are dissolved in toluene (4 mL) under a nitrogen flow. Tricyclohexylphosphine (75 mg, 0.27 mmol), tri-potassium phosphate (1.1 g, 5.38 mmol) and water (0.4 mL) are added and the reaction mixture is heated under microwave irradation (130° C.) for 2 h. At rt, water is added and the aqueous layer is extracted with DCM. Then the organic layer is washed with water and brine, separated and dried to furnish 3-cyclopropyl-2-fluoro-pyridine (200 mg, 97%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C(=O)CC[C@H]1C(O)=O>C(O)C>[O:12]([CH2:11][C:10]#[C:9][CH2:8][OH:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C(#CCOC1CCCCO1)COc1ccccc1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCO
Product: OCC#CCOc1ccccc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a solution of 2 g (0.008 mol) of 4-phenoxybut-2-yn-1-ol tetrahydropyranyl ether in 20 ml of 96% ethanol, there was added 1.02 g (0.004 mol) of Pyr/PTS. The reaction mixture was stirred for 2 hours at 55° C.; the solvent was then removed in vacuo and the residue diluted with 20 ml of water and extracted with methylene chloride. The combined extracts were dried and evaporated in vacuo. The residue was purified by column chromatography on 30 g of silica gel, using hexane-ethyl acetate (90:10) as eluant, to yield 4-phenoxybut-2-yn-1-ol, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([O:9]CC2C=CC=CC=2)[CH2:6]1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([OH:9])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)C1
Temperature: 40 °C
Yield: 94.5 %

Procedure:
A solution of trans-3-benzyloxy-cyclobutanecarboxylic acid methyl ester (680 mg, 3.09 mmol) as a 0.05 M solution in MeOH is pumped through the H-Cube™ flow hydrogenator fitted with a 10 mol % Pd/C catalyst cartridge heated to 40° C. at 10 bar. The flow rate is set at 1 ml/min. The solvent is removed under reduced pressure to give trans 3-hydroxy-cyclobutanecarboxylic acid methyl ester (380 mg, 94.5%); TLC (hexane/AcOEt, 1:1) Rf 0.38, 1H NMR (400 MHz, chloroform-d) δ ppm 2.18-2.25 (m, 2H), 2.55-2.61 (m, 2H), 3.01-3.08 (m, 1H), 3.70 (s, 3H), 4.53-4.61 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]1[CH2:9][NH:8][CH2:7]1)(=[O:4])=[O:3].[CH3:10][CH:11]([CH2:13][CH2:14][CH2:15][C@H:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C:27](=O)[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:17])[CH3:12].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.O>[CH3:1][S:2]([O:5][CH:6]1[CH2:9][N:8]([C@H:27]2[CH2:28][CH2:29][C@@:30]3([CH3:31])[C@@H:25]([CH2:24][CH2:23][C@@H:22]4[C@@H:32]3[CH2:33][CH2:34][C@@:35]3([CH3:36])[C@H:21]4[CH2:20][CH2:19][C@@H:18]3[C@H:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH:11]([CH3:10])[CH3:12])[CH2:26]2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CS(=O)(=O)OC1CNC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](N5CC(OS(C)(=O)=O)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3.50 g of the mesylate salt of 3-methanesulfonyloxyazetidine (m.p. 111.5°-113° C. dec.) and 5.46 g of 5α-cholestan-3-one in 100 ml of anhydrous methanol maintained at room temperature under a nitrogen atmosphere add 1.74 g sodium cyanoborohydride portionwise over a 20 minute period. Stir for 30 minutes at room temperature, pour into 600 ml water, add to the mixture 100 ml 1.1 M aqueous sodium bicarbonate and extract three times with ethyl ether. Combine the ether extracts, dry over 3 A molecular sieves and remove solvent in vacuo to give a mixture of α- and β-mesylates. Chromatography of this mixture on 150 g Stahl-type silica using ethyl acetate affords the pure title product (slower-moving component), m.p., 135.5° C. dec., [α]D26 =+12.1° (CHCl3, 0.4%).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([SH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>CO.C(#N)C=C>[CH2:5]([S:12][CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: SCc1ccccc1
Reactant: C=CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCCSCc1ccccc1
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
Acrylonitrile (21.4 g) was added dropwise to a solution of benzyl mercaptan (49.6 g) and triethylamine (4 ml) in methanol (400 ml). This addition lead to an exothermic reaction and the temperature of the reaction mixture was allowed to rise from room temperature to 35° C. After 10 minutes the reaction was almost complete as shown by TLC, there being a trace of unreacted thiol still present. Additional acrylonitrile (0.5 g) was then added to consume the last of the thiol. After a further 10 minutes the solution was evaporated to give the title compound 69.0 g as a pale yellow oil.
Reaction SMILES: [C:1]([CH:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:24])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:24])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:3])[CH3:2]
Reactant: CCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(C)cc3)nn12

Procedure:
Analogously to Example 1, 520 mg (1.30 mmol) of 2-acetyl-N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}heptanamide (Example 24A) and 1.99 g (13.0 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetylhexyl)-5-methyl-2-(4-methylbenzyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([OH:19])=O)[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+].C([N:24](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>O.CN(C=O)C>[CH2:1]([NH:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[S:8][C:7]=1[C:17]([NH2:24])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CC
Reactant: CCCCNc1cc(-c2ccncc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNc1cc(-c2ccncc2)sc1C(N)=O
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
A mixture of 3-(butylamino)-5-(pyridin-4-yl)thiophene-2-carboxylic acid (0.370 g, 1.34 mmol), ammonium chloride (0.717 g, 13.4 mmol), triethylamine (1.88 mL, 13.4 mmol) and DMF (8.0 mL) was stirred for 5 min. Then, 1-hydroxybenzotriazole (0.541 g, 4.00 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.767 g, 4.00 mmol) were added and stirring was continued for 3 days. The mixture was then poured into sat. aqueous sodium hydrogen carbonate (100 mL) and water (60 mL). Extraction with ethyl acetate-tetrahydrofuran (3:1, 2×100 mL), washing with sat. aqueous sodium hydrogen carbonate and brine, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a yellow solid. This solid was triturated with dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.202 g, 55%) as a yellow solid. The filtrate was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to ethyl acetate) to afford the additional title compound (0.067 g, 18%):
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[CH2:16]=[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl>[CH3:16][C:17]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:2][CH2:18]1
Reactant: C=C(C)c1ccccc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ZnEt2 (165 mL, 169 mmol) in DCM (160 mL) at 0° C. was added a solution of TFA (6.5 mL, 85 mmol) in DCM (80 mL) dropwise and the mixture was stirred at 0° C. for 30 min. Then to above mixture was added CH2I2 (6.6 mL, 85 mmol) in DCM (80 mL) dropwise and the mixture was stirred at 0° C. for 20 min, followed by adding dropwise a solution of prop-1-en-2-ylbenzene (5.0 g, 42.3 mmol) in DCM (80 mL). The mixture was stirred at rt for 30 min, quenched by brine (100 mL), extracted with DCM (2×100 mL) and the combined organic layers were dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=1/0 to 100/1) to afford compound P43a (3.4 g, 60%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].Cl[Si](C)(C)C.[CH3:19][OH:20]>>[C:6]1([CH:5]([NH2:4])[C:2]([CH3:13])([CH3:1])[C:3]([O:20][CH3:19])=[O:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CO
Reactant: CC1(C)C(=O)NC1c1ccccc1
Agent: C[Si](C)(C)Cl
Product: COC(=O)C(C)(C)C(N)c1ccccc1
Yield: 98 %

Procedure:
A solution of 15.4 g of 3,3-dimethyl-4-phenylazetidin-2-one and 14.3 g of chlorotrimethylsilane in 150 cm3 of anhydrous methanol are refluxed for 6 hours. The solution is then evaporated and ethyl acetate and aqueous sodium bicarbonate at 5% are added. The organic phase is washed with water, is dried on sodium sulphate, and is then evaporated, obtaining 17.8 g of methyl 3-phenyl-3-amino-2,2-dimethylpropanoate (yield 98%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([OH:16])[C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:7][CH:8]=1.Br[CH:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:2][C:3]1[CH:4]=[C:5]([O:16][CH:22]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21]2)[C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[N:7][CH:8]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2O)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2ncc(Br)cc2OC2CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A mixture of 5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-ol-hydrochloride (1.0 g, 3.10 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (WO 2003/062224) (1.01 g, 4.03 mmol), K2CO3 (1.29 g, 9.30 mmol), and DMF (20 mL) were reacted at 50° C. over the weekend. The reaction was cooled to room temperature, poured into water (250 mL) and extracted with EtOAc:ether (1:1). The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (40% EtOAc in hexanes) to afford tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate (584 mg, 41.4% yield) as a tan solid. 1H NMR (CDCl3) δ 8.42 (bs, 1H), 8.02 (s, 1 h), 7.10 (d, 1H), 6.42 (s, 1H), 4.95 (m, 1H), 3.75-3.44 (m, 4H), 2.35 (d, 3H), 2.21 (m, 2H), 1.50 (s, 9H); Mass spectrum (apci) m/z=456.9 (M+H).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([O:31]CC)=[O:30])[CH:25]([CH3:34])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([OH:31])=[O:30])[CH:25]([CH3:34])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CCC1C(=O)O
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-methylpiperidine-4-carboxylate (750 mg, 1.62 mmol, 1.0 eq) in THF/H2O (8/1, 9.0 mL) was added NaOH (130 mg, 3.24 mmol, 2.0 eq). The mixture was heated to 60° C. and stirred for 16 h. After cooling down to room temperature, the reaction mixture was adjusted to pH=7 with aq. HCl. The solvent was removed in vacuo to give the residue, which was purified by silica gel (DCM/MeOH=15:1) to give 1-((6-((trans-4-(tert-butyl)cyclohexyl)oxy)naphthalen-2-yl)methyl)-3-methylpiperidine-4-carboxylic acid as a white solid (620 mg, Y: 88%). ESI-MS (M+H)+: 438.3. HPLC: 100.00%; 1H NMR (400 MHz, CDCl3) δ ppm 10.82 (br, 1H), 7.65-7.54 (m, 3H), 7.41-7.40 (m, 1H), 7.04-7.02 (m, 2H), 4.20-4.14 (m, 1H), 3.85 (s, 2H), 3.15-3.07 (m, 2H), 2.77-2.71 (m, 1H), 2.50-2.46 (m, 1H), 2.18-2.16 (m, 3H), 1.96-1.92 (m, 2H), 1.81-1.78 (m, 2H), 1.36-0.96 (m, 9H), 0.82 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:27][C:26]4[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=4[N:24]=3)[CH2:18]2)[N:3]=1.[NH2:32][NH2:33]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]3[C:11]([C:12]([NH2:13])=[N:32][NH:33]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][C:26]=4[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc5c([nH]4)CCCC5)C3)nc(N)n2)cc1F
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 129.5 %

Procedure:
A mixture of 4-{2-amino-6-[2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (150 mg, 0.358 mmol) and hydrazine (1.13 mL, 35.8 mmol) in ethanol (4 mL) was heated at 120° C. under microwave conditions with stirring for 1 hour. The solvent was evaporated to get 200 mg of residue, which was purified by preparative HPLC to afford the title compound (42 mg) as a yellow powder. LC-MS (ES) m/z=432 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.71 (s, 4H), 2.42 (s, 2H), 3.12-2.99 (m, 2H), 3.66 (dt, J=11.6 Hz, 2.4 Hz, 1H), 4.00 (dd, J=11.6 Hz, 2.0 Hz, 1H), 4.33-4.30 (m, 1H), 4.44 (dd, J=10.8 Hz, 2.4 Hz, 1H), 4.62 (bs, 1H), 5.28 (s, 2H), 6.18 (s, 2H), 6.66 (s, 1H), 7.61 (dd, J=8.4 Hz, 0.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.97 (s, 1H), 11.51 (s, 1H), 11.68 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]1[N:14]=[C:15]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26]([O:33][CH3:34])[CH:25]=2)=[O:23])[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12>ClCCCl.ClCCl.O>[CH3:34][O:33][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[N+:30]([O-:32])=[O:31])[C:22]([C:15]1[N:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]2=[C:13]([NH:12][C:8](=[O:10])[CH3:9])[N:14]=1)=[O:23]
Reactant: COc1cc(C(=O)c2nc(N)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COc1cc(C(=O)c2nc(NC(C)=O)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.54 ml (3.84 mmol) of triethylamine and then 0.21 ml (2.95 mmol) of acetyl chloride are added, under a nitrogen atmosphere, to 0.8 g (2.56 mmol) of (1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitro-phenyl)methanone obtained in example 76 in 20 ml of 1,2-dichloroethane. The reaction medium is stirred at ambient temperature for 16 hours and then taken up in a mixture of dichloromethane and water. The organic phase is separated by settling, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel, elution being carried out with a dichloromethane/acetone (94/6) mixture. 0.523 g of an orange solid is collected. Melting point: 256° C.; 1H NMR (d6-DMSO): 2.14 (3H, s), 4.02 (3H, s), 7.34-7.44 (2H, m), 7.94-8.08 (3H, m), 8.09 (1H, s), 9.75 (1H, d)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH2:27]([C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH2:28][CH2:29][CH3:30]>>[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([NH:35][CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[CH:36][CH:37]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Reactant: CCCCc1ccc(N)cc1
Product: CCCCc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.24 g) and 4-butylaniline (149 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[O:16][C:15]2[C:10](=[N:11][C:12]([Cl:17])=[CH:13][CH:14]=2)[CH:9]=1.C=O.[C:20]([O-])([O-])=O.[K+].[K+]>C(O)=O>[ClH:17].[Cl:17][C:12]1[N:11]=[C:10]2[CH:9]=[C:8]([C@@H:4]3[CH2:5][CH2:6][CH2:7][N:3]3[CH3:20])[O:16][C:15]2=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2oc([C@@H]3CCCN3)cc2n1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O=CO
Product: CN1CCC[C@H]1c1cc2nc(Cl)ccc2o1

Procedure:
A 660 mg (1.04 mmol) sample of 2-(2-(S)-pyrrolidinyl)-5-chlorofuro[3,2-b]pyridine dihydrochloride, from Example 11e above, was dissolved in 5 mL of 88% formic acid and 10 mL of 37% aqueous formaldehyde and heated at reflux for 1 hour. The reaction mixture was cooled, poured into saturated K2CO3, and the mixture was extracted with CH2Cl2. The extract was dried over MgSO4, and the solvent was removed. The residue was chromatographed on silica gel, eluting with 100:0 to 95:5 CHCl3 :MeOH. The residue was converted to the salt by treatment with HCl/ether to give 540 mg of title compound: 1H NMR (D2O, 300 MHz) δ 2.28-2.38 (m, 2H), 2.49-2.72 (m, 2H), 2.92 (br s, 3H), 3.41 (m, 1H), 3.80 (m, 1H), 4.84 (m, 1H), 7.50 (d, 1H, J=8.8 Hz), 8.0 (d, 1H, J=8.8 Hz), 8.56 (d, 1H); MS m/z: 237 (M+H)+ ; Anal. Calcd for C12H13N2OCl.1.0 HCl. C, 52.07; H, 5.13; N, 10.12. Found: C, 51.85; H, 5.46; N, 9.78.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].[CH2:9]([O:11][C:12](Cl)=[O:13])[CH3:10].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:9]([O:11][C:12](=[O:13])[NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8])[CH3:10]
Reactant: CCOC(=O)Cl
Reactant: NC1CCCCC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)NC1CCCCC1O
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2-amino-cyclohexanol (3.50 g, 23.0 mmol, 1.0 eq.) in CH2Cl2 (100 mL) was added ethylchloroformate (2.65 mL, 1.2 eq.) followed by an aqueous solution of K2CO3 (16.0 g in 200 mL of H2O). The mixture was stirred vigorously for 1 h. The separated aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated to give (2-hydroxy-cyclohexyl)-carbamic acid ethyl ester (4.36 g, >100%).