Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][N:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]([C:59](=[O:64])[C:60]([F:63])([F:62])[F:61])=[CH:51]1>CN(C=O)C.O.CCOC(C)=O>[F:63][C:60]([F:61])([F:62])[C:59]([C:52]1[C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[N:50]([NH:49][C:15]([C:11]2[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:17])[CH:51]=1)=[O:64]
Reactant: Nn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C(=O)C(F)(F)F)c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (360 mg, 1.55 mmol), HOTT (628 mg, 1.69 mmol), and DIPEA (740 μL, 4.24 mmol) in DMF (10 mL) is stirred at rt under N2 for 10 min. 1-(1-Amino-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (322 mg, 1.4 mmol) is added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by HPLC reverse phase column chromatography eluting with a mobile phase of 0.1% TFA/water through 100% MeCN in a 30 min. ramp to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid [3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-amide (71 mg, 11%) as a solid. MS: 443 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 12.56 (s, 1H), 9.32 (s, 1H), 8.90 (d, 1H), 8.35 (d, 1H), 8.30-8.27 (m, 1H), 8.22-8.17 (m, 1H), 7.75-72 (m, 1H), 7.69-7.62 (m, 1H), 7.52-7.44 (m, 3H), 2.81 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[O:24][C:18]2[CH:19]([CH3:23])[NH:20][CH2:21][CH2:22][C:17]=2[CH:16]=1>>[Br:14][C:15]1[O:24][C:18]2[CH:19]([CH3:23])[N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:21][CH2:22][C:17]=2[CH:16]=1
Reactant: CC1NCCc2cc(Br)oc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2oc(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-bromo-7-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[NH:12][C@H:13]([CH2:17][OH:18])[CH:14]([CH3:16])[CH3:15])[N:10]=2)[CH2:3]1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>CN(C)C=O>[Si:20]([O:18][CH2:17][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:19])[CH:14]([CH3:16])[CH3:15])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 67.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (750 mg, 2.60 mmol) (obtained as described in Reference Example 36(3)) in dimethylformamide (38 ml) were added t-butyldimethylsilyl chloride (470 mg, 3.12 mmol) and imidazole (212 mg, 3.12 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:3) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (700 mg, yield 67%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH:18]=1)[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].O.C(=O)(O)[O-]>C(O)C.C(OCC)(=O)C>[NH2:19][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=1[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccccc1Oc1cc(Cl)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
A mixture of compound 50 (4.40 g, 14.30 mmol) and 5 nCl2.2H2O (16.13 g, 71.5 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 h. Water and saturated bicarbonate solution (˜250 ml) was added (very effervescent). The reaction mixture was diluted with ethyl acetate and then Celite® was added and the mixture was stirred for 15 min then filtered. The filtrate was extracted with ethyl acetate twice, and the organic extract was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography, dry loaded with THF onto 80 g SiO2 and eluted with 0% to 50% ethyl acetate in hexanes to afford title compound 51 (2.10 g, 51%) as a beige solid. LRMS (ESI): (calc) 277.05. (found) 278.2 (MH)+. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.46 (ddd, J=7.9, 7.4, 1.8 Hz, 1H), 7.17 (td, J=7.6, 1.2 Hz, 1H), 6.97 (dd, J=8.3, 0.9 Hz, 1H), 6.94 (dd, J=8.4, 2.3 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.05 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][CH2:16][C:17](Br)=[O:18].O>CN(C=O)C>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Cc1cnc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-methyl-pyrazin-2-ylamine and cesium carbonate (11.2 g) dissolved in dry DMF (30 mL) was added by dropwise addition bromoacetylbromide (2.89 g) and the mixture stirred at rt for 2 hours. Water (200 mL) was added and the mixture extracted with ethyl acetate (2×100 mL) and dried over magnesium sulfate. Concentration of the extract to ˜50 mL and addition of isohexane (100 mL) gave the sub-titled compound as a solid (1.64 g).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[CH3:17][CH:18]([OH:25])[CH2:19][NH:20][CH2:21][CH:22]([OH:24])[CH3:23]>CC1C=CC=CC=1C>[CH3:17][CH:18]([OH:25])[CH2:19][NH:20][CH2:21][CH:22]([OH:24])[CH3:23].[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([OH:15])(=[O:16])[CH2:11][CH2:12][C:13]([OH:8])=[O:14]
Reactant: O=C1CCC(=O)O1
Agent: CC(O)CNCC(C)O
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)CCC(=O)O
Temperature: 165 °C
Reaction time: 6 h

Procedure:
This Example describes the method used for making a reaction product of di-isopropanolamine, benzoic acid and succinic acid anhydride. A one-liter reaction flask was provided with a mechanical agitator, a thermometer and a DeanStark arrangement. 261.06 g (1.960 mol) of di-isopropanol amine (type S, BASF), 540.88 g (4.429 mol) of benzoic acid (Aldrich) and 69.69 g (0.696 mol) of succinic acid anhydride (Aldrich) were placed in the flask. A small quantity of o-xylene, approximately 60 ml, was added as entraining agent in order to remove the liberated water. The reaction mixture was kept in a nitrogen atmosphere and heated for 1 hour at 165° C., whereafter the reaction temperature was brought to 180° C. After 6 hours the temperature was reduced to 160° C. and the flask was evacuated to remove the o-xylene. After about 1 hour it was possible to tap off the reaction mixture. Analysis showed that the number-averaged molecular weight (Mn) was 583 and the weight-average molecular weight (Mw) was 733. The ratio between Mw and Mn (1.26) is indicative of the fact that a mixture of compounds has formed. In formula 1 below, the compounds that can form during the reaction between di-isopropanol amine, benzoic acid and succinic acid are diagrammatically indicated (it should be noted that formula 1 is the most probable structure of the resulting compounds). The reaction shows the formation of a mono-disperse compound. The ratio of the reactants as shown in the formula is associated with a selected value for n. This ratio need not be equal to the ratio for the overall reaction, which is, in fact, a mixture of compounds with different values for n forms. In the reaction according to this example, a ratio has been selected equal to 2.82:6.36:1 (di-isopropanol amine: benzoic acid: succinic acid anhydride). This means that there are 3×2.82=8.46 mol-equivalents of reactive NH/OH groups in the amine, against 6.36+2×1.00=8.36 mol/equivalents acid groups in the benzoic acid and anhydride. There is therefore a very small excess (about 1%) of di-isopropanol amine.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([O-:10])=O)([O-:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>N1C=CC=CC=1.C1COCC1>[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:14]([OH:17])(=[O:16])=[O:15])[CH:13]=1)[C:8]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:10])([O-:4])=[O:3]
Reactant: NCCCCCC(=O)OCc1ccccc1
Reactant: O=C([O-])c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(CCCCCNC(=O)c1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1)OCc1ccccc1
Reaction time: 2 h
Yield: 35.2 %

Procedure:
14.6 g of 3-nitro-5-sulfobenzoic acid monosodium salt were dissolved in 300 ml of pyridine and stirred for 2 hours, after which 2.2 ml of oxalyl chloride were added dropwise. After 1 hour, 16.6 g of benzyl ε-aminocaproate as a solution in 100 ml of THF were added dropwise and the mixture was stirred overnight. The mixture was concentrated on a rotary evaporator and then stirred with 100 g of strongly acid ion exchanger in 100 ml water for 50 hours. The mixture was filtered and washed with water, and the filtrate was concentrated. The residue was dissolved in 30% methanol/water, treated with 21 g of tetraethylammonium bromide and adjusted to pH 6.5 with sodium hydroxide solution. The resulting solution was chromatographed on 500 g of silanized silica gel (RP2) with 30% methanol. 8.6 g of benzyl ε-(3-nitro-5-sulfobenzoylamino)caproate were obtained in the form of the tetraethylammonium salt, which was stirred with 100 g of cation exchanger in water, filtered off and washed with water. The filtrate was concentrated and gave the corresponding free sulfonic acid. TLC (silica gel: HOAc/EtOAc=20%) Rf=0.7 (educt=0.4); TLC (silica gel: NH3/EtOH=1%) Rf=0.8 (educt=0.7); TLC (RP18: EtOH/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=60% Rf=0.4 (educt=0.8). HPLC (RP18: MeCN/Et4N+ (0.01M) phosphate buffer (0.1M; pH 6.5)=30%) tR =5.9 min. (educt=1.3 min). 1.32 g of benzyl 6-(3-nitro-5-sulfobenzoylamino)hexanoate were dissolved in 30 ml ethanol/water=60%, 100 mg of Pd/C 10% were added and the mixture was hydrogenated while stirring (magnetic stirrer). The total absorption of hydrogen (1.5 hours) was 235 ml. TLC control showed that starting material was no longer present. In the TLC the amine is present practically at the start. The catalyst was filtered off and the solution was concentrated to dryness on a rotary evaporator. The IR control of the substance showed the complete absence of the original nitro group and of the benzyl group. The resulting 6-(3-amino-5-sulfobenzoylamino)hexanoic acid was used directly for the preparation of the azide.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][CH:18]1[CH2:22][O:21][C:20](=[O:23])[CH2:19]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][CH:18]1[CH2:19][C:20](=[O:23])[O:21][CH2:22]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CC(CO)CO1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C1CC(COS(=O)(=O)C(F)(F)F)CO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of trifluoromethanesulfonic anhydride (15.0 g, 53.2 mmol) in DCM (25 mL) was added dropwise to a solution of 4-(hydroxymethyl)dihydrofuran-2(3H)-one (4.75 g, 41.0 mmol) and 2,6-lutidine (7.15 mL, 61.4 mmol) in DCM (111 mL) at 0° C. The mixture was stirred at 0° C. for 20 minutes. The product mixture was diluted with DCM (100 mL) and was washed with water (3×100 mL). The organic phase was dried over magnesium sulfate and evaporated under vacuum.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH:13]=O>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1/[CH:13]=[N:9]/[NH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: NNc1ccc(I)cc1
Reactant: O=Cc1c(F)cccc1Cl
Solvent: CCO
Product: Fc1cccc(Cl)c1/C=N/Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 75 %

Procedure:
To a solution of (4-iodophenyl)hydrazine (1.0 g, 4.27 mmol) in ethanol (10 mL) was slowly added solution of 2-chloro-6-fluorobenzaldehyde (0.675 g, 4.27 mmol) in ethanol (10 mL). The reaction mass was stirred at RT for 5-6 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was concentrated to afford 1.2 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 6.87 (d, J=8.4 Hz, 2H), 7.26-7.36 (m, 3H), 7.53 (d, J=9.0 Hz, 2H), 8.06 (s, 1H), 10.84 (s, 1H). MS (m/z): 374.87 (M)+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl.[N:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[N:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])=[CH:16][CH:15]=1
Reactant: ClCc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Under anhydrous conditions (positive nitrogen pressure, presence of 3Å molecular sieves), a mixture of N-hydroxyphthalimide (15.0g, 0.091mole), 4-picolylchloride hydrochloride (15.0g, 0.091mole), and triethylamine (27.7g, 0.273 mol) in 125 ml of anhydrous acetonitrile was refluxed for 2 hours. After stirring overnight at ambient temperature, TLC showed that the starting materials were practically consumed. Ethyl acetate (500 ml) was added, mixture stirred for 15 min and filtered. The solvent was evaporated and the residue dissolved in 1L of EtOAc. The filtrate was washed with water (2×500 ml), brine (1×500 ml), dried (MgSO4), and evaporated to a smaller volume (100ml). The mixture was cooled down to -18° C., precipitate filtered and recrystallized from EtOAc/hexane to afford 13.2g (56.8%) of title product.
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=[O:7].[Na+].[Br:10][C:11]1[CH:24]=[CH:23][C:14]2[C:15]3[CH:21]=[CH:20][C:19](N)=[CH:18][C:16]=3[S:17][C:13]=2[CH:12]=1>O>[Br:10][C:11]1[CH:24]=[CH:23][C:14]2[C:15]3[CH:21]=[CH:20][C:19]([OH:7])=[CH:18][C:16]=3[S:17][C:13]=2[CH:12]=1
Reactant: Nc1ccc2c(c1)sc1cc(Br)ccc12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c(c1)sc1cc(Br)ccc12
Temperature: 2 °C
Reaction time: 3 h

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 209.3 g of concentrated sulfuric acid and 8.93 g of NaNO2 in a nitrogen atmosphere, and cooled to 2° C. Then 24.0 g of the intermediate 7-bromodibenzothiophene-3-yl-amine prepared in Example 1-3 was added, and stirred at 2 to 4° C. for 3 hours. The resulting mixture together with 99.8 g of water was poured into 348.7 g of 65 wt % sulfuric acid preheated to 80° C., stirred at 80 to 85° C. for 5 hours, and cooled to room temperature. The reactant was filtered, extracted six times with 300 ml of ethyl acetate, and vacuum concentrated. The concentrate was purified by silica gel chromatography using chloroform as an eluting solvent to obtain 7.11 g of objective 7-bromodibenzothiophene-3-ol. The 1H-NMR spectrum data and the results of elemental analysis of the product are shown below:
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reaction time: 4 h

Procedure:
To a round-bottom flask was added tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 125-3 (3.4 g, 11 mmol), Pd/C (0.5 g) and methanol (100 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flushed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 125-4 as purple solid. MS m/z 279.2 (M+1).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([Cl:23])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][OH:19])=[C:16]([Cl:23])[CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCOc1ccc(CO)c(Cl)c1

Procedure:
According to customary procedures, 4-dodecyloxy-2-chlorobenzoic acid synthesized in the same manner as described in Referential Example 15 was reduced with LiAlH4 to obtain 4-dodecyloxy-2-chlorobenzyl alcohol, and this compound was brominated with PBr3 to obtain 4-dodecyloxy-2-chlorobenzyl bromide. In the same manner as described in Referential Example 18, 2.0 g of the so-obtained compound was reacted with 1.0 g of 4-acetoxyphenol to obtain 4-dodecyloxy-2-chlorobenzyl(4-acetoxyphenyl) ether. Then, the acetyl group was removed by an equimolar amount of LiOH, whereby 0.9 g of 4-dodecyloxy-2-chlorobenzyl(4-hydroxyphenyl) ether was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6][CH:7]=1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH2:34])=[N:31][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH:34][C:17]([C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[N:11][N:12]3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:16]=2)=[O:19])=[N:31][CH:32]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc3c2cnn3-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc3c2cnn3-c2ccccc2)nc1

Procedure:
4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid was reacted with C-(5-methyl-pyrazin-2-yl)-methylamine in the presence of EDCI, HOBt and NMM using the procedure of step 4 of Example 1 to provide 4-(5-Methyl-pyridin-2-yl)-1-phenyl-1H-indazole-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide, MS (M+H)=435.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[CH3:10][C:11]([CH3:13])=[CH2:12].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl>[C:11]([O:7][C:6]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:9])[NH:1]1)=[O:8])([CH3:13])([CH3:12])[CH3:10]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A pressure flask is charged with (S)-(−)-2-pyrrolidone-5-carboxylic acid (25 g, 193.6 mmol) and dichloromethane (100 mL) and the stirred suspension is cooled in a dry ice acetone bath. Liquid 2-methylpropene (150 mL) is added followed by concentrated sulfuric acid (0.5 mL). The pressure flask is sealed and the reaction mixture is stirred at room temperature for 48 h. The pressure flask is cooled in a dry acetone bath and the reaction mixture is diluted with dichloromethane (500 mL) and treated with a saturated solution of sodium bicarbonate until the effervescence is ceased. The organic layer is separated, washed with saturated solution of sodium bicarbonate (300 mL), brine (300 mL), dried over anhydrous Na2SO4 and solvent removed in vacuo to give the title compound as a white crystalline solid. The crude material is used without purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]([C:19]2[C:20]([CH3:32])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)=[N:23][CH:24]=2)=[O:18])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CCN(CC)CC.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl.CCOC(C)=O>[CH3:48][S:49]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][NH:16][C:17]([C:19]1[C:20]([CH3:32])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[N:23][CH:24]=1)=[O:18])(=[O:51])=[O:50]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NCc1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NCc1cccc(CNS(C)(=O)=O)c1
Reaction time: 2.5 h
Yield: 63.1 %

Procedure:
To a solution of [3-({[2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (0.05 g, 0.111 mmol) in DCM (2 mL) at 0° C. is added TFA (0.013 mL. 0.111 mmol) and the mixture is stirred for 2.5 hours. The mixture is concentrated in vacuo. The residue is dissolved in THF (2 mL). Et3N (0.05 mL, 0.333 mmol) and methanesulfonyl chloride (0.010 mL, 0.133 mmol) are added and the mixture is stirred for 12 hours. The mixture is diluted with EtOAc (100 mL), washed with saturated aqueous NH4Cl (2×50 mL), dried with Na2SO4, filtered, and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid 3-(methanesulfonylamino-methyl)-benzylamide (0.03 g, 64%) as a powder. MS: 429 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.65 (s, 3H), 2.86 (s, 3H), 4.18 (d, J=6.3 Hz, 2H), 4.50 (d, J=5.9 Hz, 2H), 7.27-7.45 (m, 3H), 7.62 (m, 2H), 8.13 (m, 1H), 8.28 (m, 1H), 8.90 (s, 1H), 9.25 (m, 1H); IC50=48.5 nM.