Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH2:43]([C:47]1[O:51][N:50]=[CH:49][C:48]=1[C:52](O)=[O:53])[CH2:44][CH2:45][CH3:46]>CN(C=O)C>[CH2:43]([C:47]1[O:51][N:50]=[CH:49][C:48]=1[C:52]([N:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1)=[O:53])[CH2:44][CH2:45][CH3:46]
Reactant: c1cncc(C2CCNC2)c1
Reactant: CCCCc1oncc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1oncc1C(=O)N1CCC(c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
A solution of 3-pyrrolidin-3-yl-pyridine (15 mg, 0.1 mmol), TBTU (48 mg, 0.15 mmol, 1.5 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.1 mmol) in DMF (0.6 mL) was added to 5-butylisoxazole-4-carboxylic acid (17 mg, 0.1 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C17H21N3O2: 299.1634, found 299.1635.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][CH:14]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13][CH:14]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2nc(Cl)cc(Cl)n2)cn1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(-c2nc(Cl)cc(N3CCOCC3)n2)cn1

Procedure:
N-(5-(4,6-dichloropyrimidin-2-yl)pyridine-2-yl)pivalamide (975 mg, 3.0 mmol), morpholine (0.262 mL, 3.0 mmol) and triethylamine (502 mL, 3.6 mmol) are stirred in NMP (10 mL) for 2 hours at 85° C. At this time the reaction mixture is partitioned between EtOAc (200 mL) and NaHCO3(sat.) (50 mL). The organic layer is separated, washed with water (30 mL), then brine (30 mL), dried over Na2SO4, filtered, concentrated, obtaining the desired product.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([C:25]#[N:26])=[N:15][C:14]=2[N:13]([CH3:27])[C:11]1=[O:12])(=[O:3])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[C:1]([O:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([CH2:25][NH2:26])=[N:15][C:14]=2[N:13]([CH3:27])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CCOCn1c(C#N)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOCn1c(CN)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Yield: 105.4 %

Procedure:
A suspension of (R)-1-(5-acetoxyhexyl)-8-cyano-7-ethoxymethyl-3-methylxanthine (750 mg, 1.92 mmol) and 10% palladium on carbon (250 mg) in glacial acetic acid (40 ml) was treated with hydrogen gas (80 psi) on a Parr shaker for 3 hours. The mixture was filter through a pad of celite and then the filtrate was concentrated under reduced pressure to provide the acetic acid salt of (R)-1-(5-Acetoxyhexyl)-8-aminomethyl-7-ethoxymethyl-3-methylxanthine (800 mg, 91% yield) as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)[O:5][CH2:4][CH2:3]1.[Cl-].[NH4+]>C1COCC1.O.[Fe]>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:14]=[CH:15][C:16]([NH2:19])=[CH:17][N:18]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1CCOc2cccc(Oc3ncc([N+](=O)[O-])cn3)c21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCOc2cccc(Oc3ncc(N)cn3)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
2-[(4-methyl-3,4-dihydro-2Hchromen-5-yl)oxy]-5-nitropyrimidine (Intermediate 216, 192 mg, 0.668 mmol) was dissolved in 9.0 mL of a 2/1 THF/water solution. Iron (187 mg, 3.34 mmol) and ammonium chloride (179 mg, 3.34 mmol) were added and the reaction mixture was stirred for 24 h at room temperature. After dilution with AcOEt and filtration over a celite pad (washing with AcOEt), the organic phase was washed (two times) with an aqueous saturated solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and evaporated and the residue was purified by flash chromatography on silica gel using cyclohexane/ethyl acetate from 1:0 to 0:1 as eluents affording the title compound (144 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cncnc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cncnc4)CC3)cnc12
Yield: 25.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(pyrimidin-5-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.14 g, 0.29 mmol) obtained in step 2 and methanesulfonamide (0.138 g, 1.45 mmol), the title compound (0.04 g, 26%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].[CH3:24][C:25]([OH:29])([CH:27]=[CH2:28])[CH3:26]>C(Cl)Cl>[OH:29][C:25]([CH3:26])([CH3:24])[CH:27]=[CH:28][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: C=CC(C)(C)O
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(Br)cc12
Solvent: ClCCl
Product: CC(C)(O)C=Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
Obtained by a procedure similar to that described in Example 1, using 5-bromo-3-(2-phthalimidoethyl)-1H-indole (which was prepared as described in U.S. Pat. No. 4,252,803) and 2-methylbut-3-en-2-ol, as a foam. Rf 0.10 (SS 8). Found: C,72.31; H,6.09; N,.7.16. C23H22N2O3 ; 0.15 CH2Cl2 requires C,71.82; H,5.81; N,7.23%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:26])[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C@H:15]([NH:19][C:20]([NH2:22])=[S:21])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:25])[CH3:24])=[CH:4][CH:3]=1.[Cl:27][CH2:28][C:29](=O)[CH2:30]Cl>CC(C)=O>[Cl:27][CH2:28][C:29]1[N:22]=[C:20]([NH:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[C:14]([N:11]2[CH2:12][CH2:13][C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([OH:26])[C:9]([CH3:24])([CH3:25])[CH2:10]2)=[O:23])[S:21][CH:30]=1
Reactant: CC(C)[C@@H](NC(N)=S)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: O=C(CCl)CCl
Solvent: CC(C)=O
Product: CC(C)[C@@H](Nc1nc(CCl)cs1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
To a suspension of 1-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)thiourea (29 mg, 0.073 mmol) in acetone (300 μL) was added 1,3-dichloropropan-2-one (14 mg, 0.105 mmol) and the reaction mixture was stirred overnight at rt. The solvents were removed and the residue purified via column chromatography (SiO2, 25% EtOAc/hep then 50% EtOAc/hep then 10% EtOAc with 0.06% DIPEA). (R)-2-(4-(chloromethyl)thiazol-2-ylamino)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one (35 mg, >95% yield) was isolated as a clear glass. HPLC purity: >99%, rt 3.87 min; MS found: 470.22 (M+)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[C:4]([C:19](=O)[CH3:20])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:19]([C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)[CH3:20]
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-1-(4-hydroxypiperidin-1-yl)-2-naphthyl]ethanone (74 mg, 0.24 mmol) and ammonium acetate (188 mg, 2.44 mmol) in methanol (1.4 mL) and acetonitrile (1.4 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (30.6 mg, 0.487 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C17H22ClN2O (M+H)+: m/z=305.1; Found: 305.1.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>ClCCl>[CH3:25][CH:24]([CH3:26])[C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)=[O:27]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Triethylamine (976 mg, 9.66 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (1.00 g, 4.83 mmol) in dichloromethane (20 mL) at 0° C. and stirred for 30 min. Isobutyryl chloride (617 mg, 5.79 mmol) was then added and the mixture was warmed to ambient temperature and stirred for 4 h. the reaction mixture was quenched with ice-water and the organic layer separated. The aqueous layer was extracted with dichloromethane (5×5 mL) and the combined organic layers were washed water, saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 2-methyl-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-1-one (1.20 g, 90%) as a yellow solid.
Reaction SMILES: [Cl-].[C:2]([O-:5])(=[O:4])[CH3:3].[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH3:21])[CH:16]=[C:17]([F:20])[CH2:18]O)=[CH:11][CH:10]=1)[CH3:7].C1C=CC=CC=1>N1C=CC=CC=1>[C:2]([O:5][CH2:18][C:17]([F:20])=[CH:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:6][CH3:7])=[CH:14][CH:13]=1)([CH3:21])[CH3:22])(=[O:4])[CH3:3]
Reactant: CCOc1ccc(C(C)(C)C=C(F)CO)cc1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCOc1ccc(C(C)(C)C=C(F)COC(C)=O)cc1
Yield: 99 %

Procedure:
The method of Example 11 was repeated using acetate chloride (0.17 ml), 4-(4-ethoxyphenyl)-2-fluoro-4-methylpent-2-enol (Example 9) (86 mg), benzene (4 ml) and pyridine (0.04 ml) to yield the title compound (0.1 g, 99%).
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].[ClH:11].[CH2:12]([OH:14])[CH3:13]>C(Cl)(Cl)Cl>[ClH:11].[CH2:12]([O:14][C:1](=[NH:10])[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:13]
Reactant: N#Cc1ccccc1C#N
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccccc1C#N
Temperature: 0 °C

Procedure:
A suspension of phthalonitrile (70 g, 0.55 mol) in ethanol (100 ml) and chloroform (200 ml) was warmed and then cooled to 0° C. The reaction mixture was saturated with HCl (g) and then aged at 0° C. for 2 weeks. The resultant precipitate was filtered and washed with chloroform. Dilution of the filtrate with ether produced additional 2-cyano-benzimidic acid ethyl ester hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O.C(OCC)(=O)C.CCCCCC>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1c([N+](=O)[O-])c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
A solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.0 g) in concentrated sulphuric acid (10 ml) at 0° C. was treated with fuming nitric acid (9 ml) during 15 minutes, keeping the temperature at 5°-15° C. After 30 minutes the mixture was poured onto excess ice, and the precipitated solid was filtered off and dissolved in ethyl acetate. After drying over anhydrous magnesium sulphate, filtration, and evaporation in vacuo a brown oil was obtained. This oil was dissolved in the minimum of ethyl acetate and diluted with hexane. A pale yellow solid crystallized and this was discarded. The filtrate was evaporated in vacuo to give a solid which was recrystallized from toluene-hexane to furnish a yellow solid. One further recrystallization from the same solvent pair gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitro-3-trifluoromethylpyrazole as white crystals, m.p. 214°-215° C.
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1([CH3:30])[CH2:29][CH2:28][NH:27][CH2:26]1>C(OCC)(=O)C>[CH2:6]([O:10][C:11]1[CH:16]=[C:15]([N:27]2[CH2:28][CH2:29][C:25]([CH3:30])([CH3:24])[CH2:26]2)[N:14]=[CH:13][N:12]=1)[C:7]#[C:8][CH3:9]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CC1(C)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCC(C)(C)C2)ncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
Into 4 ml of N,N-dimethylformamide was resolved 0.37 g of 4-(2-butynyloxy)-6-chloropyrimidine, 0.56 g of potassium carbonate and 0.2 g of 3,3-dimethylpyrrolidine was added therein, and the mixture was stirred for 6 hours at 80° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.11 g of 4-(2-butynyloxy)-6-(3,3-dimethylpyrrolidin-1-yl)pyrimidine (hereinafter, referred to as Compound (27)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[Li+].[CH3:26]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)([CH3:26])[CH3:6])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-benzyloxy-indol-1-yl)-propionic acid ethyl ester (20 g, 61.5 mmol) in THF (180 mL) is added LDA (2.0 M toluene, 37 mL) dropwise at −78° C. After the addition of LDA, the mixture is stirred for 30 min, then methyl iodide (8.77 g, 122.6 mmol) is added. The reaction mixture is allowed to warm to room temperature, after stirred for 2 hrs, quenched by water, extracted with ethyl acetate, dried over sodium sulfate. Concentration yields the title compound.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[N+]([O-])=O)[CH:2]([CH3:4])[CH3:3].N([O-])=O.[Na+].[ClH:20]>O>[Cl:20][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3])[CH:9]=[O:10]
Reactant: CC(C)Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)Cc1ccc(C=O)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
4-Isobutyl-3-nitrobenzaldehyde (3.3 g, 0.0159 mol) is added to a solution of stannous chloride (8.37 g, 0.0441 mol) in concentrated hydrochloric acid (23 mL) at 0-5° C. The reaction mixture is slowly brought to 60-65° C. and is stirred at this temperature for 30 minutes. The reaction mixture is again cooled to 0-5° C. During cooling formation of solid is observed which is broken before proceeding further. Solution of sodium nitrite (1.36 g, 0.0188 mol) in demineralized water (3 mL) is added to the above reaction mixture at 0-5° C., allowed to stir for 10 minutes at this temperature. It is then poured into a slurry of cuprous chloride (3.6 g, 0.0346 mol) in demineralized water (5 mL) at 60-65° C. & stirred for 20 minutes. The reaction mixture is extracted in ethyl acetate (2×30 mL). Combined organic layer is dried over sodium sulfate and concentrated to get the crude, which is purified using column chromatography (230-400 mesh; toluene:n-hexane, 3:7) to yield 3-chloro-4-isobutylbenzaldehyde.
Reaction SMILES: [S:1]=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[Br:10]Br>C(OCC)(=O)C>[Br:10][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:1][N:9]=1
Reactant: N#Cc1ccc[nH]c1=S
Reactant: BrBr
Solvent: CCOC(C)=O
Product: Brc1nsc2ncccc12
Temperature: 25 °C

Procedure:
To a solution of 2-thioxo-1,2-dihydropyridine-3-carbonitrile (2.1 g, 15.44 mmol) in ethyl acetate (50 mL), bromine (5.9 g, 37.11 mmol) was added drop wise at 0° C. The reaction mixture was allowed to warm to room temperature and then refluxed for 3 h. The reaction mixture was concentrated under reduced pressure. Trituration with hexanes:methylene chloride (1:1) mixture gave 3-bromoisothiazolo[5,4-b]pyridine, as light brown solid which was carried forward without further purification. MW=215 confirmed by LC-MS, tr=16.08 min (Method Y) MH+=216.
Reaction SMILES: [Br-].[O:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Zn+])=[CH:6][CH:5]=1)[CH3:3].I[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:23][CH:24]=2)=[C:15]([CH3:34])[CH:14]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:3][O:2][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:13]2[CH:14]=[C:15]([CH3:34])[C:16]([C:20]3[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[S:23][CH:24]=3)=[C:17]([CH3:19])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COc1ccc(C[Zn+])cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1

Procedure:
A THF solution of 4-methoxylbenzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-(4-methoxybenzyl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide: 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=5.2 Hz, 2 H), 7.66 (d, J=4.9 Hz, 2 H), 7.11 (d, J=8.4 Hz, 2 H), 6.86 (d, 2 H), 6.80 (s, 1 H), 6.75 (s, 2 H), 3.80 (s, 2 H), 3.78 (s, 2 H), 1.98(s, 6 H); ESI-MS: m/z 399.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[CH3:2].[N:24]1([CH2:33][C:34](O)=[O:35])[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])(=[O:12])=[O:11])[C:34](=[O:35])[CH2:33][N:24]1[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-])C(=O)Cn1cc(C)c(=O)[nH]c1=O
Yield: 91.2 %

Procedure:
The title compound (2.35 g, 91%) was synthesized by the reaction of N-[2-(4-fluoro-2-nitro-benzenesulfonylamino)-ethyl]-glycine ethyl ester (1.76 g, 5 mmol) and (thymin-1-yl)-acetic acid (0.92 g, 5 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 11.30 (s, 0.6H), 11.27 (s, 0.4H), 8.28˜8.05 (m, 2.8H), 7.78 (m, 1.2H), 7.31 (s, 0.6H), 7.23 (s, 0.4H), 4.65 (s, 1.2H), 4.47 (s, 0.8H), 4.30 (s, 0.8H), 4.16 (q. 0.8H), 4.07 (q. 1.2H), 4.00 (s, 1.2H), 3.49 (t, 1.2H), 3.22 (q, 1.2H), 3.12˜3.01 (m, 1.6H), 1.75 (s, 3H), 1.23 (t, 1.2H), 1.18 (t, 1.88H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([N:9]2[CH:13]=[C:12]([NH2:14])[N:11]=[CH:10]2)[CH2:5]1.[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][CH:29]([CH2:33][CH2:34][CH3:35])[C:30](O)=[O:31])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1>>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([N:9]2[CH:13]=[C:12]([NH:14][C:30](=[O:31])[CH:29]([NH:28][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:33][CH2:34][CH3:35])[N:11]=[CH:10]2)[CH2:5]1
Reactant: CC(C)(C)CN1CCC(n2cnc(N)c2)C1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(CC(C)(C)C)C2)cn1

Procedure:
1-[1-(2,2-Dimethyl-propyl)-pyrrolidin-3-yl]-1H-imidazol-4-ylamine was coupled with 2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 18.9, 28.6, 33.0, 33.4, 35.9, 43.1, 53.1, 55.7, 57.3, 63.5, 68.3, 102.6, 102.8, 103.1, 106.6, 112.3, 112.5, 112.6, 132.1, 137.7, 138.8, 161.9, 164.5, 169.1; MS m/z 476.2 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18])([CH3:15])[CH3:14].[CH3:22][O:23][CH2:24]Cl>C1COCC1>[CH:13]([C:16]1([CH2:22][O:23][CH3:24])[CH2:21][CH2:20][O:19][C:17]1=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)C1CCOC1=O
Reactant: COCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC1(C(C)C)CCOC1=O
Temperature: -70 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of diisopropylamine (13.1 mL) in THF was treated dropwise with butyl lithium (58.4 mL of 1.6M solution in hexanes) at −10° C. Then the reaction mixture was cooled to −70° C. and treated dropwise with 2-isopropyl-γ-butyrolactone (9.30 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the mixture was stirred for 3 h at −70° C., then warmed-up to −40° C. and treated dropwise at this temperature with chloromethyl methyl ether (7.50 mL). After that, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature for 80 h. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, then washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 7.00 g (57%) of the title compound.