Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[NH:9][N:8]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:38][C:37]([C:39](O)=[O:40])=[CH:36][CH:35]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:10]1[N:9]([C:39]([C:37]2[S:38][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:35][CH:36]=2)=[O:40])[N:8]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(C(=O)O)s1
Reactant: Oc1ccccc1C1CC(c2cnccn2)=NN1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(C(=O)N2N=C(c3cnccn3)CC2c2ccccc2O)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.4 %

Procedure:
A solution of 2-(3-pyrazin-2-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (0.10 g, 4.2 mmol), 5-(2-([(tert-butoxycarbonyl)amino]methyl)phenyl)thiophene-2-carboxylic acid (0.134 g, 4.02 mmol), and EDCI (0.116 g, 6.06 mmol) in DCM (4 mL) was allowed to stir at rt for 6 h. The reaction was quenched by the addition of water and the organic and aqueous solutions were separated. The aqueous solution was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl [2-(5-{[5-(2-hydroxyphenyl)-3-pyrazin-2-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzyl]carbamate (0.50 g, 23%). LCMS: (FA) ES+ 556.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[C:8]1[C:13]([C:14]([O-])=[O:15])=[C:12](C)[C:11]([C:18]([O-])=[O:19])=[C:10](C)[C:9]=1[C:22]([O-])=[O:23].O.[OH-].[Na+]>C1COCC1>[OH:15][CH2:14][C:13]1[CH:12]=[C:11]([CH2:18][OH:19])[CH:10]=[C:9]([CH2:22][OH:23])[CH:8]=1
Reactant: Cc1c(C(=O)[O-])c(C)c(C(=O)[O-])c(C)c1C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(CO)cc(CO)c1
Yield: 92.6 %

Procedure:
A 3-liter, round-bottom flask equipped with an overhead stirrer, an addition funnel and a reflux condenser was charged with lithium aluminum hydride (49.7 grams, 1.31 mol) and anhydrous THF (500 ml) under nitrogen atmosphere. The resulting suspension was slowly heated to reflux and a solution of trimethyl-1,3,5-benzenetricarboxylate (100.0 grams, 0.40 mol) in anhydrous THF (1.0 liter) was added dropwise thereto while maintaining a gentle reflux (3 hours). The resulting gray suspension was stirred under reflux for additional 7 hours and then cooled in an external ice-water bath. The excess lithium aluminum hydride was hydrolyzed by dropwise addition of water (50 ml, 45 minutes), then 15% NaOH (50 ml, slow stream), and finally more water (150 ml, slow stream). The resulting suspension was stirred at ambient temperature for 14 hours. The solids were filtered off and the filtrate was concentrated under high vacuum to obtain a colorless oil which slowly solidified to afford 1,3,5-tris(hydroxylmethyl)benzene (62.3 grams, 94%) as a white solid. The 1H NMR and 13C NMR spectra were consistent with the assigned structure.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][NH:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][N:28]([CH3:27])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: CNCCO
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CN(CCO)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and 2-methylamino-ethanol. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 452.4 (MH+).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=O.ClC(N(C)C)=C(C)C.CCN(C(C)C)C(C)C.[NH:30]1[C:38]2[C:33](=[C:34]([C:39]3[CH:40]=[C:41]([NH2:54])[C:42]4[C:46]([CH:47]=3)=[N:45][N:44](C3CCCCO3)[CH:43]=4)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1.CC1C=CC(S(O)(=O)=O)=CC=1.N>C1COCC1.CO>[NH:30]1[C:38]2[C:33](=[C:34]([C:39]3[CH:47]=[C:46]4[C:42]([CH:43]=[N:44][NH:45]4)=[C:41]([NH:54][C:10]([C:2]4[CH:3]=[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][N:5]5[N:1]=4)=[O:12])[CH:40]=3)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1cc2ccccn2n1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cc2ccccn2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyrazolo[1,5-a]pyridine-2-carboxylic acid (27 mg, 0.166 mmol) was treated with anhydrous THF (2 ml) and then 1-chloro-N,N, 2-trimethylpropenylamine (0.026 ml, 0.20 mmol). The reaction was stirred at room temperature under nitrogen for 2 hrs. The reaction was then treated with anhydrous DIPEA (0.131 ml, 0.753 mmol) and 2 ml of solution of 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (750 mg, 2.26 mmol) in THF (30 ml). The reaction was then stirred at room temperature under nitrogen for 69 hrs. The solvent was blown-off under a stream of nitrogen, dissolved in methanol (3 ml) and then solvent removed under reduced pressure. The crude reaction mixture was dissolved in methanol (5 ml), treated with Macroporous Tosic Acid (4.45 mmol/g, 102 mg, 0.45 mmol), stirred at room temperature for 17 hrs and then treated with 0.88 ammonia (0.5 ml), stirred for 30 minutes and then filtered. The solvent was removed under reduced pressure and then the residue purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:20][NH2:21]>C(O)C>[CH3:20][NH:21][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CN
Reactant: CC(=O)N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(C2CCN(C(C)=O)CC2)cc1

Procedure:
Reaction of 4-(1-acetylpiperidin-4-yl)benzenesulphonyl chloride (16.0 g) [the product of Example 2(i)] with an excess of aqueous methylamine (100 ml, 30%) in ethanol (10 ml) according to the method of Example 2(ii) gave the title compound, (15.0 g), used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:18][O:19][CH3:20])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([CH2:18][O:19][CH3:20])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added methyl 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 27.4, 50 mg, 0.19 mmol) and sodium hydroxide (31 mg, 0.76 mmol) in methanol/water (3 mL/3 mL). The resulting solution was stirred for 12 hours at room temperature. The pH of the solution was adjusted to 1-2 with hydrogen chloride (6 M), then concentrated under reduced pressure to yield 150 mg (crude) of the title compound as the HCl salt as white solid.
Reaction SMILES: [NH2:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[C:3](OCC)=[O:4].[BH4-].[Na+]>O.C(O)C>[NH2:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(N)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(N)(CO)c1cccs1
Yield: 84.2 %

Procedure:
The product of Example 437A (0.497 g, 2.494 mmol) in 1:3 v/v water/ethanol (12 mL) was reacted with sodium borohydride (0.481 g, 12.47 mmol) at reflux for 4 hours. The reaction was concentrated by rotary evaporation partition between water (5 mL), ethyl ether (25 mL), 1N aqueous sodium hydroxide (1.25 mL). Solid sodium chloride was added to saturate separate phases. The aqueous was re-extracted with ethyl ether (25 mL). The combined ethereal extracts were washed with brine (25 mL), dried over potassium carbonate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.330 g, 2.099 mmol, 84%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.35 (s, 3 H) 1.96 (s, 2 H) 3.33-3.42 (m, 2 H) 4.91 (t, J=5.70 Hz, 1 H) 6.89-6.95 (m, 2 H) 7.28 (dd, J=3.49, 2.76 Hz, 1 H). MS (DCI) m/z 158 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=1.N([O-])=O.[Na+].[OH-].[Na+].[OH-].[NH4+].[BrH:24]>O1CCOCC1.O.[Cu]Br>[Br:24][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][N:10]=2)[CH:4]=1
Reactant: Nc1ccc(F)c(-c2ccc(F)cn2)c1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(-c2cc(Br)ccc2F)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Fluoro-3-(5-fluoropyridin-2-yl)phenylamine (1.2 g) was dissolved in 1,4-dioxane (4 ml) and 48% aqueous hydrobromic acid (30 ml). The solution was cooled to 0° C. A solution of sodium nitrite (478 mg) in water (6 ml) was added dropwise with stirring to maintain an internal temperature below 4° C. The mixture was then aged a further 1 h at 4° C. A solution of copper(I) bromide (2.58 g) in 48% aqueous hydrobromic acid (10 ml) was then added slowly to retain a reaction temperature below 5° C. The resulting mixture was then stirred at 5-10° C. for 1 h, ambient temperature for 0.5 h and then heated at 50° C. for 0.5 h. The mixture was then cooled to 4° C., and made basic by addition of 4 N aqueous sodium hydroxide (106 ml), followed by 30% aqueous ammonium hydroxide (40 ml). The mixture was extracted with ethyl acetate, the organic phase dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was chromatographed (silica gel, 70% CH2Cl2/isohexane) to afford 2-(5-bromo-2-fluorophenyl)-5-fluoropyridine: 1H NMR (400 MHz, DMSO) δ 8.74 (1H, dd, J 2, 1 Hz), 8.05 (1H, dd, J 7, 3 Hz), 7.90 (2H, m), 7.69 (1H, m), 7.38 (1H, dd, J 11, 9 Hz); MS (ES+) m/z 270, 272.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH3:15][CH2:16][CH2:17]Br>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH2:15][CH2:16][CH3:17])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])ccc(O)c1Cl
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc([N+](=O)[O-])c(C)c1Cl
Yield: 44.8 %

Procedure:
Treatment of 2-chloro-3-methyl-4-nitrophenol (15.5 g, 82.7 mmol) with sodium hydride (50%, 4.37 g, 91.0 mmol) and n-propyl bromide (11.2 g, 91.0 mmol) in DMF (300 ml) and subsequent workup as described in 1 (a) gave 2-chloro-3-n-propyloxy-6-nitrotoluene (8.50 g), m.p. 42°-3° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[ClH:8].[CH3:9][O:10][C:11]1[CH:33]=[CH:32][C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH:19]3[CH2:24][O:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[S:17][C:13]=2[CH:12]=1>C1COCC1>[ClH:8].[ClH:8].[CH3:9][O:10][C:11]1[CH:33]=[CH:32][C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:1](=[O:3])[CH3:2])[CH2:20][CH:19]3[CH2:24][O:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[S:17][C:13]=2[CH:12]=1
Reactant: COc1ccc2nc(N3CCNCC3COc3cccnc3)sc2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2nc(N3CCN(C(C)=O)CC3COc3cccnc3)sc2c1
Temperature: 70 °C
Yield: 85 %

Procedure:
Acetic anhydride (0.100 mL) was added to a solution of 6-methoxy-2-(2-((pyridin-3-yloxy)methyl)piperazin-1-yl)benzo[d]thiazole hydrochloride (73.2 mg, 0.186 mmol) in THF (2 mL), and the mixture was heated to 70° C. for 2 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were brought to pH 12 with 1 N NaOH and were extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 74.3 mg (85%) of the title compound as a white solid. LC-MS: RT=6.10 min, [M+H]+=399.0.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[N:27])[CH:24]=3)[N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>[Pd].C(O)C.O1CCCC1>[C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:18]=[C:17]2[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)#[N:27]
Reactant: CS(=O)(=O)n1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c2cc(C#N)ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)n1cc(C2CCNCC2)c2cc(C#N)ccc21
Reaction time: 2 h
Yield: 97 %

Procedure:
10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Pd]
Solvent: c1ccccc1
Product: COC(=O)CCc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
To a solution of methyl ester 2.3 (52 mg, 0.125 mmol) in benzene (5 ml), was added 10 mg of 10% Pd-C. The atmosphere was evacuated and flushed with H2 gas (3×), and the solution stirred for 1.5 h. The mixture was filtered and concentrated to give 52 mg (100%) of 6.1. MS (ESI) 419.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:9])=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.[CH2:24]=[O:25].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:9])=[C:6]([CH:7]=1)[CH2:24][OH:25]
Reactant: C=O
Reactant: C[C@@H](NC(=O)C(C)(C)C)c1ccc(Br)cc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)C(C)(C)C)c1ccc(Br)cc1CO
Reaction time: 4 h
Yield: 66.9 %

Procedure:
In 10 ml of tetrahydrofuran is dissolved 2 g of N-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to this solution is dropwise added 14.3 ml of phenyllithium (1.48 M cyclohexane-diethyl ether solution), after which the temperature of the resulting mixture is elevated to −5° C. and the mixture is stirred at the same temperature for 4 hours. Subsequently, 1.06 g of paraformaldehyde is added thereto and the mixture is stirred at 5° C. for 1 hour, after which 6 ml of water is added to the reaction mixture and the organic layer is separated. The organic layer obtained is dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. The residue obtained is purified by silica gel chromatography (eluant; n-hexane:ethyl acetate=2:1) to obtain 1.48 g (yield: 66.9%) of 5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl alcohol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1.C(Cl)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+].CC([O-])(C)C.[K+].C(O[Na])(C)(C)C.S1(CCCC1)(=O)=O>C(C(C)=O)C.CC(C)=O.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([O:16][CH2:34][C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Reactant: BrCc1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Solvent: O=S1(=O)CCCC1
Solvent: CCC(C)=O
Solvent: ClCc1ccccc1
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F

Procedure:
5-(Benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid can be protected by acid or hydroxyl protection reagent (such as BnBr, BnCl) at ambient temperature in the presence of base (includes Na2CO3, K2CO3, NaHCO3, KHCO3, t-BuOK, t-BuONa) in appropriate inert solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer acetone and methyl ethyl ketone). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). Benzyl 5-(benzyloxy)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+].[N].[N]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[CH3:21][C:22]1[CH:23]=[N:24][N:25]([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[CH:7][C:8]=3[O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[CH:3]=2)[CH:26]=1
Reactant: Cc1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cnn(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Yield: 29.3 %

Procedure:
A mixture of 197 (300 mg, 0.86 mmol, scheme 42), 4-methyl-1H-pyrazole (69 mg, 0.86 mmol), CuI (16.4 mg, 0.086 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (24.4 mg, 0.172 mmol) [J. C. Antilla, A. Klapars, et. al. JACS, 2002, 124, 11684-1688] and K2CO3 (238 mg, 1.72 mmol) in toluene (1.7 mL) was stirred at room temperature in an atmosphere of nitrogen nitrogen overnight, diluted with EtOAc (100 mL), filtered through a Celite® pad, and concentrated under reduced pressure. The residue was purified by flash chromatography with gradient elution with EtOAc/hexane (1:1) to EtOAc/hexane (2:1) to afford title compound 256 (88.8 mg, 37% yield) as a white solid. MS (m/z): 352.06 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16](=[O:17])[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.C(N(CC)CC)C.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:25]([OH:28])(=[O:27])[CH3:26].[OH:1][CH2:2][C:3]1[C:16](=[O:17])[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=c1c(CO)cnc2c3ccccc3ccn12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)O
Temperature: 25 °C

Procedure:
To 3.0 g of 3-(hydroxymethyl)-4H-pyrimido [2,1-a]isoquinolin-4-one (13.3 mmole) suspended in 100 ml chloroform with 10 ml of triethylamine and a trace of 4-dimethylaminopyridine was added 5.0 g of acetic anhydride (50.0 mmole). The reaction mixture was refluxed for 2 hours, then cooled to room temperature and washed twice with water. The organic layer was dried and concentrated in vacuo to give a crude solid which was crystallized from methylene chloride/hexane to yield 3-(hydroxymethyl)-4H-pyrimido[2,1-a]isoquinolin-4-one acetate as yellow crystals (2.09 g, 59% yield) of the formula: ##STR22## having a melting point of 173.3° C. and the following elemental analysis:
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([C:27]([CH3:35])([CH3:34])[C:28]([O:30]C(C)C)=[O:29])[N:26]=4)[N:23]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]4[N:22]([CH:24]=[C:25]([C:27]([CH3:35])([CH3:34])[C:28]([OH:30])=[O:29])[N:26]=4)[N:23]=3)[CH2:13][CH2:14]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)OC(=O)C(C)(C)c1cn2nc(NCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(NCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 84.8 %

Procedure:
565 mg of isopropyl 2-[6-[2-[4-(diphenylmethoxy) piperidino]ethylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 4 ml of ethanol; 2.04 ml of a 1 N aqueous sodium hydroxide solution was added, followed by refluxing for 20 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and ajusted to pH 5.5 by the addition of 1 N hydrochloric acid. Ethyl acetate was added; the crystal precipitated was collected by filtration, washed with water and ethyl acetate and dried to yield 443 mg of the title compound.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=2[CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([N:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:8]=1[CH3:14])(=[O:19])[CH3:18]
Reactant: Cc1cc(I)ccc1NC1CCCC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(I)cc1C)C1CCCC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.5 g (1.7 mmol) of 4-cyclopentylamino-3-methyl-iodobenzene are dissolved in 20 ml tetrahydrofuran and after the addition of 81.3 mg (1.7 mmol) of sodium hydride (50% in oil) stirred for 1 hour at 40 ° C. After cooling to ambient temperature 0.1 ml (1.5 mmol) of acetyl chloride is added and the mixture is stirred overnight at ambient temperature. The solvent is distilled off and the residue distributed in water/ethyl acetate. The combined organic extracts are dried, concentrated by evaporation and chromatographed on silica gel, eluting with dichloromethane/ethanol 0 to 5%.