Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O:4][CH2:5][C@H:6]1[O:11][C@@H:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@H:9]([O:19]C(C)=O)[C@@H:8]([O:23]C(C)=O)[C@H:7]1[O:27]C(C)=O)=O.CO.C[O-].[Na+]>C(O)(=O)C>[CH:16]1[CH:15]=[CH:14][C:13]([O:12][C@@H:10]2[O:11][C@H:6]([CH2:5][OH:4])[C@H:7]([OH:27])[C@H:8]([OH:23])[C@H:9]2[OH:19])=[CH:18][CH:17]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](Oc2ccccc2)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 5 h
Yield: 76.6 %

Procedure:
To phenyl-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (21.2 g) were added methanol (120 ml) and 28% sodium methylate (0.28 ml) and the mixture was refluxed with stirring for 5 hours. After the reaction solution was cooled, acetic acid (0.1 ml) was added and the mixture was stirred for 30 minutes. Concentration of the reaction solution and crystallization with ethanol (180 ml) gave 9.8 g (yield 77%) of phenyl-β-D-galactopyranoside. Melting point: 154.5° C.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7]([OH:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.S(OC)(O[CH3:15])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:15][O:8][C:7](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10]
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1C
Yield: 75.3 %

Procedure:
o-Toluic acid (500 mg, 3.67 mmol), dimethyl sulfate (695 mg, 5.51 mmol), and K2CO3 (558 mg, 4.04 mmol) were placed in a round bottom flask and diluted with acetone (10 mL). After purging the resulting suspension with argon for 5 min, the mixture was heated to reflux for 2 h. The reaction mixture was cooled and concentrated under reduced pressure to remove acetone. After adding water to the mixture, the solution was extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Hex/EtOAc=9:1) to give 2-methylbenzoic acid methyl ester (Formula 4) (415 mg, 75%) as a white solid. Rf=0.5 (Hex:EtOAc=9:1); 1H NMR (300 MHz, CDCl3): δ 7.91 (dd, J=8.4 and 1.8 Hz, 1H), 7.40 (td, J=7.5 and 1.5 Hz, 1H), 7.24 (m, 2H), 3.89 (s, 3H), 2.60 (s, 3H).
Reaction SMILES: [CH2:1](Br)[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][NH:19]2)=[C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:14]=1>CN(C)C=O>[Cl:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:15]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:14]=1
Reactant: CC(C)CBr
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 103.4 %

Procedure:
N,N-Dimethylformamide (60 ml), isobutyl bromide (2 ml, 18 mmol), and potassium carbonate (3 g) were added to 2-chloro-6-morpholin-4-yl-9H-purine (5 g, 17 mmol) and the resulting mixture was stirred at 80° C. for 5 hours. The reaction mixture was cooled and partitioned with ethyl acetate and water and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.2 g, 100%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](=[O:19])C(F)(F)F)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:20].[K+]>CCO>[CH2:1]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([OH:19])=[O:20])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1nc(C(=O)C(F)(F)F)c2ccccn12
Agent: [K+]
Solvent: CCO
Product: CCCCc1nc(C(=O)O)c2ccccn12
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.9 %

Procedure:
To a solution of 1-(3-butyl-imidazo[1,5-a]pyridin-1-yl)-2,2,2-trifluoro-ethanone (400 mg, 1.48 mmol) in EtOH (10 mL) was added KOH (830 mg, 14.8 mmol). The mixture was stirred at ambient temperature for 15 h. After this time the mixture was concentrated, diluted with water (10 mL) and acidified to pH 3 with 2N HCl. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to yield the title compound (200 mg, 62%). 1H NMR (DMSO-d6) δ 12.1 (1H), 8.38 (1H), 7.99 (1H), 7.18 (1H), 6.90 (1H), 2.99 (2H), 1.75 (2H), 1.38 (2H), 0.92 (3H); m/z (M+H)=219.0.
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.[ClH:25]>C(Cl)Cl>[ClH:25].[ClH:25].[CH3:24][C@H:4]1[C:5]2[C:10]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:9][CH:8]=[N:7][C:6]=2[C@H:2]([OH:1])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21

Procedure:
tert-Butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was treated with HCl (4M in dioxane, 2 mL) in DCM (5 mL) for 6 hours to give (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride. MS (APCI+) [M+H] +235.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[O:8][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1ccc(OCC(=O)c2ccccc2)c(Br)c1

Procedure:
equimolar amounts of 3-bromo-4-hydroxytoluene and α-bromoacetophenone are refluxed in benzene in the presence of potassium carbonate to provide α-(2-bromo-4-methylphenoxy)acetophenone in the usual manner.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=2[O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:28][CH:29]=2)=[CH:9][CH:8]=1)[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCCCOc1ccc(C)cc1-c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C)cc1-c1ccc(COc2ccc(C(CC(=O)OCC)c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 45.2 (48 mg, 0.166 mmol), 4′-Bromomethyl-2-butoxy-5-methyl-biphenyl (67 mg, 0.2 mmol) and cesium carbonate (81 mg, 0.25 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with dilute HCl, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The residue obtained after concentration was flash chromatographed on silica gel to obtain 45.3 (71 mg).
Reaction SMILES: Br[CH:2]1[CH:8](Br)[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4](=[O:22])[CH2:3]1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:10]([N:5]1[CH2:6][CH:7]=[CH:8][CH:2]=[CH:3][C:4]1=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCN1CCC(Br)C(Br)CC1=O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN1CC=CC=CC1=O
Reaction time: 20 h
Yield: 177.4 %

Procedure:
A solution of 3.4 g (7.72 mmol) of 4,5-dibromo-1-dodecylazacycloheptan-2-one in 5.79 g (0.054 mol) of 2,6-lutidine was refluxed for 3 hours. After standing at room temperature for 20 hours, toluene was added, and the solution was filtered. The filtrate was concentrated in vacuo and distilled to give 3.8 g of a crude oil which was subjected to flash chromatography (silica gel; 3:1 petroleum ether/ether V/V) to yield pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].N.C([O-])(=O)C1C(=CC=CC=1)C([NH2:21])=O.[NH4+]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:10]([NH2:21])=[O:11])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: NC(=O)c1ccccc1C(=O)[O-]
Agent: N
Agent: [NH4+]
Product: NC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
3-Nitrophthalic anhydride (10.0 g, 50 mmol) was added in portions over 20 minutes to concentrated aqueous ammonia solution (15 ml), and the mixture was stirred at 30° C. for a further 30 minutes. The crystalline mass of ammonium phthalamate, deposited upon cooling the pale yellow solution, was collected and redissolved in a minimum amount of warm water. Concentrated hydrochloric acid (4.5 ml) was added dropwise, with stirring, and the resulting paste was washed with water, and dried in vacua to give 3-nitrophthalamic acid as a fine white powder. (9.01 g, 83%), m.p. 217° C. Found: C, 45.76; H, 2.79; N, 13.21. C8H6N2O5 requires C, 45.71; H, 2.86; N, 13.33%; vmax/cm−1 3466.52, 3321.84, 1668.64, 1604.98, and 1525.89; δH (d6-DMSO, 200 MHz) 7.75 (1H, br s, CONH), 7.8 (1H, t, Ar-5H), 8.16 (1H, brs, CONH), 8.2 (1H, d, Ar-6H), 8.3 (1H, d, Ar-4H); δC (d6-DMSO) 127.32, 130.06, 132.28, 133.49, 134.78, 147.71, 166.25, and 166.60; m/z (EI) 192 (M+−1), 177, 149, 103, 75.
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>O1CCCC1>[C:1]([O:4][CH:5]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCCCCCCO)c1coc([Si](C)(C)C)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCCCCCCCCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(1-acetoxy-9-hydroxynonyl)-2-trimethylsilylfuran (0.075 g, 0.221 mmol) and pyridine (0.056 g, 0.662 mmol) in tetrahydrofuran (2 ml) under argon at 0° was added dropwise acetyl chloride (0.052 g, 0.662 mmol). The mixture was warmed to room temperature, stirred for one hour, quenched with water and extracted into ethyl ether. The organic portion was washed with 10% hydrochloric acid, saturated sodium bicarbonate, aqueous 5% cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to an oil. Purification by flash chromatography (silica, 5 to 10% ethyl acetate/hexane) gave the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])([CH3:33])([CH3:32])[CH3:31]>C(Cl)(Cl)Cl>[C:30]([O:34][C:35](=[O:42])[NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNS(=O)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.1 %

Procedure:
The compound (1.4396 g) obtained in Example 24-2 was dissolved in anhydrous chloroform (28 ml) and then added with triethylamine (0.689 ml), followed by ice-cooling. Then, the solution was added with (4-aminobutyl)-carbamic acid t-butyl ester (852.9 mg) and stirred at room temperature for 2.5 hours. After the reaction, the solution was washed with water and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (1.4440 g) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([S:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 126.4 %

Procedure:
A mixture of N-methyl-3-(2,4-difluorophenylthio)-4-nitrobenzamide (0.68 g), iron powder (0.68 g) and ammonium chloride (68 mg) in ethanol (8 ml) and water (4 ml) was stirred and refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated to give pale yellow crystals of N-methyl-4-amino-3-(2,4-difluorophenylthio)benzamide (0.78 g).
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH2:22][C@H:21]3[CH2:24][O:25][CH3:26])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.[ClH:29]>C(Cl)Cl.O1CCOCC1>[CH3:26][O:25][CH2:24][C@@H:21]1[CH2:22][CH2:23][N:20]1[C:13]1[N:14]2[C:18]([N:19]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:28][CH2:27][C:12]=13)=[CH:17][CH:16]=[N:15]2.[ClH:29]
Reactant: COC[C@@H]1CCN1c1c2c(nc3ccnn13)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC[C@@H]1CCN1c1c2c(nc3ccnn13)CCNCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 60.1 mg (0.155 mmol) (S)-10-(2-methoxymethyl-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 3 mL DCM was added 2 mL (3.1 mmol) HCl in dioxane (4 M) and the reaction was stirred at room temperature for 5 hours. The solvent was evaporated to give the desired product as a HCl salt.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.[H-].[Na+]>N1C=CC=CC=1>[O:7]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Brc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: c1ccc(Oc2ccsc2)cc1
Yield: 73 %

Procedure:
Cuprous chloride (3.08 g, 31.1 mmol) and phenol (8.78 g, 93.3 mmol) were sequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol) in pyridine (150 ml). Sodium hydride (3.73 g, 93.3 mmol, 60% dispersion in mineral oil) was then slowly added. The reaction was heated at reflux for 20 hours under Argon. The pyridine was removed under reduced pressure. The residue was diluted with Et2O (200 ml) and washed with 1N NaOH (3×100 ml), 1N HCl (2×150 ml) and 1N NaOH (150 ml). The organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was chromatographed using hexanes to give 3-phenoxy-thiophene as a clear oil (4.0 g, 74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(C)c3)CC2)c(C)c1
Yield: 100.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-3-methylbenzoic acid (25 g) and 1-(2,4-dimethylphenyl)piperazine (22 g), the title compound (45 g) was obtained.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>Cl.C(O)C>[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:15]=[CH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CN(N)c1ccccc1
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Solvent: CCO
Product: CN(N=Cc1cccc2ccccc12)c1ccccc1

Procedure:
3.1 g of 1-naphthaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude 1-naphthaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 3.1 g (59.6%) of light yellow needle-like crystals which melt at 92.5°-94.9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O1CCCC1.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[N:7]1([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([NH:1][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:3][CH:4]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(CN3CCOCC3)cc2)CC1
Reaction time: 72 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrahydrofuran (10 mL) and tert-butyl 4-oxo-1-piperidinecarboxylate (0.60 gm) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring 3 days, the mixture is concentrated under reduced pressure. The residue is partitioned between dichloromethane and dilute aqueous sodium hydroxide. The aqueous is back-extracted with additional portions of dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is flash column chromatographed on silica gel eluting with 2% to 6% methanol in dichloromethane to afford 0.96 g of tert-butyl 4-[4-(4-morpholinylmethyl)anilino]-1-piperidinecarboxylate as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][N:15]([C:20](Cl)=[O:21])[CH2:14]1>>[CH3:12][CH:13]1[O:18][CH:17]([CH3:19])[CH2:16][N:15]([C:20]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:20]([N:15]3[CH2:16][CH:17]([CH3:19])[O:18][CH:13]([CH3:12])[CH2:14]3)=[O:21])[N:7]=2)=[O:21])[CH2:14]1
Reactant: CC1CN(C(=O)Cl)CC(C)O1
Reactant: Oc1n[nH]c2cc(F)ccc12
Product: CC1CN(C(=O)Oc2nn(C(=O)N3CC(C)OC(C)C3)c3cc(F)ccc23)CC(C)O1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 280.3 mg (1.578 mmol) of 2,6-dimethylmorpholine-4-carbonyl chloride. Yield: 16 mg (3%), M+H+: 435.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=C(OC)N=1.[CH3:21][O:22][C:23]1C(OC)=C(C=O)C=C[N:24]=1>>[CH3:21][O:22][C:23]1[C:3]([O:2][CH3:1])=[C:8]([CH:9]([OH:18])[C:10]#[C:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:24]=1
Reactant: COc1ccc(C(O)C#Cc2ccccc2)c(OC)n1
Reactant: COc1nccc(C=O)c1OC
Product: COc1nccc(C(O)C#Cc2ccccc2)c1OC
Yield: 86 %

Procedure:
Following the procedure used to prepare 1-(2,6-dimethoxy-pyridin-3-yl)-3-phenyl-prop-2-yn-1-ol, 2,3-dimethoxy-pyridine-4-carbaldehyde was reacted to give the title compound (1.08 g, 86%) as a white solid. LCMS (Method A): RT=4.11 min, [M+H]+=270.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].[Na].Cl>C1COCC1.[Na]>[OH:10][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:13][CH2:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: OCCOCCOCCO
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To triethyleneglycol (17.6 g, 117.20 mmol, 3.00 equiv) in anhydrous THF (70 mL), was added sodium (30 mg, 1.25 mmol, 0.03 equiv). Tert-butyl acrylate (5.0 g, 39.01 mmol, 1.00 equiv) was added after the sodium had dissolved. The resulting solution was stirred overnight at room temperature and then neutralized with 1.0 N hydrogen chloride. After removal of the solvent, the residue was suspended in 50 mL of brine and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (9.6 g) was isolated as a colorless oil, which was used directly for the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([N+:16]([O-])=O)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N>CCO>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ncccc1Nc1cc(F)cc(F)c1
Agent: Cl
Agent: N
Solvent: CCO
Product: Nc1ncccc1Nc1cc(F)cc(F)c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
To a solution of (3,5-difluorophenyl)-(2-nitro-pyridin-3-yl)-amine (900 mg, 3.58 mmol) in EtOH (10.7 mL) was added stannous chloride dihydrate (3.23 g, 14.33 mmol) and 35% HCl (0.5 mL). The reaction mixture was stirred at 75° C. for 2 h, when it was basified using aqueous ammonia and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide N3-(3,5-Difluorophenyl)-pyridine-2,3-diamine: 1H NMR (400 MHz, DMSO-d6) δ 5.703 (br s, 2H), 6.227-6.289 (m, 2H), 6.383-6.442 (m, 1H), 6.564-6.595 (m, 1H), 7.333 (dd, J=1.6 Hz, J=1.6 Hz, 1H), 7.784-7.791 (m, 2H); LC-MS (ESI) m/z 222.0 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([NH:33][C:34]([NH2:36])=[NH:35])[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25]>CC#N>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([S:24]([CH3:23])(=[O:25])=[O:26])[CH:28]=3)[N:35]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: CS(=O)(=O)c1cccc(NC(=N)N)c1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nc(N)sc1-c1ccnc(Nc2cccc(S(C)(=O)=O)c2)n1

Procedure:
By condensation of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine and N-(3-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=13.1 min (0-60% MeCN, purity>97%). 1H-NMR (DMSO-d6) δ: 2.55 (s, 3H, CH3), 3.19 (s, 3H, CH3), 6.97 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.47 (m, 1H, Ph-H), 7.54 (t, 1H, J=7.5 Hz, Ph-H), 8.08 (m, 1H, Ph-H), 8.34 (brs, 1H, Ph-H), 8.40 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.86 (sbr, 2H, NH2). MS (ESI+) m/z 362.38 [M+H]+ (C15H15N5O2S2 requires 361.44).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[N:5][CH:4]=1)=O.[NH2:18][C:19]1[C:20]([F:32])=[CH:21][C:22]([F:31])=[C:23]([CH:30]=1)[C:24]([NH:26][CH:27]1[CH2:29][CH2:28]1)=[O:25]>>[CH:27]1([NH:26][C:24]([C:23]2[C:22]([F:31])=[CH:21][C:20]([F:32])=[C:19]([NH:18][CH2:1][C:3]3[S:7][C:6]([NH:8][C:9]4[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=4)=[N:5][CH:4]=3)[CH:30]=2)=[O:25])[CH2:28][CH2:29]1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Reactant: O=Cc1cnc(Nc2ccc(C(=O)O)cn2)s1
Product: O=C(O)c1ccc(Nc2ncc(CNc3cc(C(=O)NC4CC4)c(F)cc3F)s2)nc1
Yield: 95 %

Procedure:
6-(5-Formyl-thiazol-2-ylamino)-nicotinic acid (see Example 19) was treated with 5-amino-2,4-difluoro-N-cyclopropylbenzamide in manner similar to the preparation of Example 6 to afford the title compound in 95% yield. LC/MS; (M+H)+=446