Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]2[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[CH3:30].Cl.[CH3:32][NH:33][OH:34]>CN(C=O)C>[CH3:30][C:15]1[C:14]([CH3:13])=[CH:19][CH:18]=[CH:17][C:16]=1[NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[C:27]([N:33]([OH:34])[CH3:32])=[O:28]
Reactant: CNO
Reactant: Cc1cccc(Nc2ccccc2C(=O)O)c1C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ccccc2C(=O)N(C)O)c1C
Temperature: 24 °C
Reaction time: 20 h

Procedure:
1,1'-Carbonyl-diimidazole (5.35 g; 0.033 mol) is added to a solution of mefanamic acid (7.2% g; 0.03 mol) in dry DMF (100 ml). The solution is stirred at 24° C. for 20 hours and then briefly warmed to 50° C. N-Methylhydroxylamine hydrochloride (2.7 g; 0.032 mo) is added to the cooled solution at 24° C. and stirred for two days. The reaction mixture is then evaporated to dryness and the residue is taken up in CH2Cl2, washed with water, and dried over sodium sulfate and evaporated. The residue is flash chromatographed through silica gel and eluted with n-hexane-CH2Cl2 -EtOAc (2:1:1) yielding a crude product which is rechromatographed through silica gel and eluted with n-hexane-CH2Cl2 -EtOAc (4:5:1). The product is recrystallized from n-pentane to give white crystals. Yield 1.5 g (18.5%); mp 70°-71° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:8][N:9]([C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]([Cl:22])[N:16]=2)[CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=O.C(O)C>C(O)(=O)C>[Cl:22][C:17]1[N:18]=[CH:19][C:20]2[NH:21][C:3](=[O:2])[C:5]3([CH2:7][CH2:6]3)[CH2:8][N:9]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:15]=2[N:16]=1
Reactant: COC(=O)C1(CN(c2nc(Cl)ncc2N)C2CCCC2)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CC2
Yield: 98 %

Procedure:
A mixture of 0.2224 g (0.00068 mole) of 1-{[(5-amino-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-cyclopropanecarboxylic acid methyl ester (V-53), 12 mL of ethanol and 0.3 mL of acetic acid was heated at reflux for 18 hours, and then concentrated under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and washed successively twice with 15 mL of aqueous sodium bicarbonate, twice with 15 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.195 g of 2-chloro-9-cyclopentyl-8,9-dihydro-spiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VI-53), as a light yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:38](=[O:39])[CH2:37][C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: O=C(Cl)Cc1cccs1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)Cc3cccs3)c3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate and 2-thiophenacetyl chloride as a pink oil (92%). 1H NMR (CDCl3, 300 MHz) δ 7.61 (dd, J=6.2, 2.5 Hz, 1H), 7.44 (m, 4H), 7.17 (m, 5H), 7.07 (m, 1H), 6.97-6.88 (m, 2H), 6.70 (d, J=3.0 Hz, 1H), 4.90 (s, 2H), 3.94 (s, 31), 3.65 (s, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). M1(ESI): 540.1. HPLC, Rt: 5.72 min (Purity: 99.2%).
Reaction SMILES: [NH2:1][C:2]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[C:7]([C:2]1([NH:1][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3]1)#[N:8]
Reactant: CCCCC(=O)Cl
Reactant: N#CC1(N)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NC1(C#N)CCCC1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
To 11.0 g (0.1 mol) of 1-amino-1-cyanocyclopentane dissolved in 100 ml of dichloromethane, 15 ml 10.9 g (0.1 mol) of triethylamine was added, then dropwise 13 ml, 13 g (0.1 mol) of valeroyl chloride, while keeping the temperature at 25-35° C. The reaction mixture was stirred at 30-35° C. for 2 hours, then it was washed with water. The phases were separated, the organic phase was evaporated to obtain the pure title compound as an oil. The compound was identified by elementary analysis, IR, NMR and GC-MS spectomety.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:17][C:18]([OH:20])=[O:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([OH:3])=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(OC(=O)C)(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:17][C:18]([OH:20])=[O:19])[CH2:4][C:1]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:3])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[Carboxymethyl(4-methoxybenzenesulfonyl)amino]acetic acid (0.5 grams, 1.65 mmol) in acetic anhydride (15 mL) was dissolved in acetic anhydride by gentle warming. The resulting solution was stirred at room temperature overnight. The acetic anhydride was removed by evaporation under vacuum; the residue was dissolved in methylene chloride and morpholine (0.16 mL, 1.82 mmol) was added. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid solution, water and brine, dried over magnesium sulfate and concentrated to afford [(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetic acid as an oil, 0.33 grams (54%).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH3:13][O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:25])[CH:16]([Br:33])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1cccc(OC)c1

Procedure:
AIBN (10 mg) was added to a solution of (3-Methoxy-phenyl)-acetic acid methyl ester (2 g, 11 mmol) in CCl4 (30 ml). The solution was then heated to reflux and NBS (2.3 g, 13 mmol) was added in portions. After complete addition the reaction mixture was refluxed for 4 h. After cooling, solid residue was filtered off and the filtrate concentrated to yield product Bromo-(3-methoxy-phenyl)-acetic acid methyl ester, that was washed repeatedly with pet ether.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][S:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)(=[O:22])=[O:21]>CC#N>[CH3:19][S:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1)(=[O:22])=[O:21]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CS(=O)(=O)Oc1ccc(CCN)cc1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCc2ccc(OS(C)(=O)=O)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 86.9 %

Procedure:
A mixture of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.15 g, 0.52 mmol), 4-(2-aminoethyl)phenyl methanesulfonate (0.14 g, 0.63 mmol) and TEA (0.07 g, 0.68 mmol) in MeCN (1.5 ml) was heated in a microwave reactor at 120° C. for 35 mins. 4-(2-Aminoethyl)phenyl methanesulfonate (0.07 g) was added to the mixture, and it was heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was evaporated and the crude product was purified by flash column chromatography using hexane and EtOAc, 80:20-30:70, as eluant to yield the title compound (0.21 g, 85%). 1H NMR (500 MHz, CDCl3): δ 1.57-1.59 (m, 6H), 2.50-2.61 (m, 2H), 3.12-3.16 (m, 5H), 4.39-4.42 (m, 1H), 5.23 (brm, 1H), δ 6.80-6.83 (m, 2H), 7.12-7.15 (m, 2H), 7.48-7.54 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 14.4, 20.4, 35.5, 37.6, 45.0, 47.8, 107.8, 122.4, 125.2, 129.1, 130.1, 130.3, 131.8, 135.2, 137.0, 148.2, 158.6; Mass Spectrum: M−H+ 463.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([O:20][CH2:21][CH3:22])(=[O:19])[C:10]1[CH:18]=[CH:17][C:15]([OH:16])=[C:12]([O:13][CH3:14])[CH:11]=1.N1C=CN=C1>O1CCCC1>[Si:1]([O:16][C:15]1[CH:17]=[CH:18][C:10]([C:9]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:12]=1[O:13][CH3:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.7 %

Procedure:
Tert-butyldimethylsilyl chloride (14 g) was added to a mixture of ethyl vanillate (15 g), imidazole (13 g) and tetrahydrofuran (100 ml) and the mixture was stirred at ambient temperature for 48 hours. The mixture was filtered and evaporated to give ethyl 4-(tert-butyldimethylsilyloxy)-3-methoxybenzoate (25.1 g). A solution of the product so obtained in tetrahydrofuran (50 ml) was cooled to -70° C. and to this was added a cooled (-70° C.) solution of thiazol-2-yl-lithium prepared by adding 2-bromothiazole (14.1 g) to a mixture of n-butyl-lithium (1.5M in hexane, 57.3 ml) and diethyl ether (30 ml) which had been cooled to -70° C. The mixture was stirred for 16 hours and allowed to warm to ambient temperature. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×100ml). The combined extracts were washed with water and with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained 4-hydroxy-3-methoxyphenyl 2-thiazolyl ketone (4.5 g) in 24% yield, m.p. 103° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][O:13][C:14]1[CH:15]=[C:16](OB(O)O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:17]=[CH:16][CH:15]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2cnc3ccccc3c2)c1
Reaction time: 19 h
Yield: 70 %

Procedure:
The compound is prepared by the reaction of 3-bromoquinoline (200 mg, 0.96 mmol, 1.06 eq) and 3-methoxyphenylboric acid (138 mg, 0.91 mmol, 1 eq) according to method A in 19 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 3/1 yields the desired product in a yield of 70% (147 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:13][CH:12]=1)=O.CO.[BH4-].[Na+]>O>[CH2:1]([NH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)c1ccc(Sc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Sc2ccc(CNCc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Combine benzylamine (17 mg, 0.16 mmol), 6-(4-formyl-phenylsulfanyl)-nicotinamide (40 mg, 0.16 mmol), 3 Å molecular sieves (0.1 g), and methanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (25 mg, 0.64 mmol) to the reaction and stirred at room temperature for 1 hour. Pour the reaction into water then extract with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (50 mg). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 6-[4-(benzylamino-methyl)-phenylsulfanyl]-nicotinamide, (24 mg): m/z=349.99(M+1); 1H NMR (MeOD, 300.00 MHz): (8.84 (dd, 1H, J=2.3, 1.0 Hz), 8.02 (dd, 1H, J=8.6, 2.3 Hz), 7.66-7.49 (m, 4H), 7.66-7.49 (m, 4H), 7.42-7.34 (m, 5H), 6.99-6.92 (m, 1H), 3.88-3.77 (m, 4H). HPLC=99% @ 5.82 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. By the method of Example 7 the following compounds were prepared, isolated as the free base except where noted:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].I.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[NH:22])SC)=[CH:14][CH:13]=1)#[N:11]>O.C(O)C>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[NH:22])[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:16][CH:17]=1)#[N:11]
Reactant: CSC(=N)Nc1ccc(C#N)cc1
Reactant: NCCC(=O)O
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(NC(=N)NCCC(=O)O)cc1
Yield: 64.1 %

Procedure:
A mixture of 4.18 g (47 mmol) of β-alanine, of 1,88 g (47 mmol) of sodium hydroxide in 20 cm3 of water and of 15 g (47 mmol) of N-(4-cyanophenyl)-S-methylisothiourea hydroiodide in 100 cm3 of 95% ethanol is heated to reflux for 5 hours. The precipitate formed is filtered, then dissolved in 150 cm3 of 1N aqueous sodium hydroxide solution. The solution obtained is washed with ethyl acetate (3×50 cm3), then neutralized to pH 7 by a concentrated HCl solution. The precipitate obtained is filtered, washed with hot absolute ethanol, then recrystallized in water. 7 g (yield 65%) of N-[4-cyanophenylamino(imino)methyl]-3-aminopropanoic acid, having a melting point of 233°-235° C., are obtained.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][CH2:9][CH:10]([O:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:22]([O:21][CH:10]([CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:9][O:8][CH2:7][C:6]([OH:30])=[O:5])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)COCC(COC(=O)c1ccccc1)OC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCC(COCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
130 g (336.4 mmol) of the title compound of Example 7a is dissolved in 200 ml of dichloromethane, and 100 ml of trifluoroacetic acid is added at 0° C. It is stirred for 4 hours at room temperature and then evaporated to the dry state. The residue is crystallized from pentane/diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:24][N:25](C)C)[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:35]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:35][NH:25][CH:24]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccccc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2ccccc2)ccn1
Yield: 86 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 18.4 g (50.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-phenyl-2-propen-1-one obtained in Example 20-1) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 14.5 g of the title compound as a white powder. (Yield: 86%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][O:21][C:22]([CH2:23][CH3:24])=[O:25]
Reactant: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Yield: 70.6 %

Procedure:
A solution of 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)isoindolin-1-one (50 mg, 0.18 mmol), propionyl chloride (16 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in dichlorometane was stirred at 25° C. for 3 hrs. The reaction solution was washed with water, dried, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 43 mg of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CO)CCCCCBr
Yield: 101.4 %

Procedure:
According to the method for the synthesis of 206e, 205g (43.0 g, 0.16 mol) was treated with LiBH4 (5.55 g±0.25 mol) and methanol (7.75 g, 0.24 mol) in CH2Cl2 (200 mL) to give 206g (36.2 g, 98%) as a colorless, viscous oil. 1H NMR (CDCl3): δ 3.41 (t, 2H, J=6.9), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m, 6H), 0.86 (s, 6H). 13C NMR (CDCl3): δ 71.9, 38.6, 35.1, 34.1, 32.9, 29.2, 24.0, 23.2. HRMS (LSIMS, nba): Calcd for C9H28Br (MH+−H2O): 205.0592, found: 205.0563.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8]O)[NH:4][N:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Br:11][CH2:8][CH2:7][C:5]1[NH:4][N:3]=[C:2]([NH2:1])[CH:6]=1
Reactant: BrP(Br)Br
Reactant: Nc1cc(CCO)[nH]n1
Solvent: ClCCl
Product: Nc1cc(CCBr)[nH]n1
Temperature: -10 °C
Yield: 47.9 %

Procedure:
To a solution of 2-(3-amino-1H-pyrazol-5-yl)ethanol (13 g, 102.2 mmol) in DCM (200 mL) was added PBr3 (83 g, 306.7 mmol). The reaction mixture was heated under reflux for 3 h and then cooled to −10° C. and carefully quenched with aq satd Na2CO3 (200 mL). The resulting mixture was extracted with DCM (3×200 mL), and the Na2CO3 (200 mL). The resulting mixture was extracted with DCM (3×200 mL) combined organic layers were washed with brine, dried over anhydrous Na2SO4, and then concentrated in vacuo to give 5-(2-bromoethyl)-1H-pyrazol-3-amine (9.3 g, 48%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:4][C:3]1([Cl:6])[Cl:5].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[Cl:1][C:2]1([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[CH2:4][C:3]1([Cl:6])[Cl:5]
Reactant: O=C(O)C1(Cl)CC1(Cl)Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)C1(Cl)CC1(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 9.47 g (0.05 mole) of 1,2,2-trichlorocyclopropane carboxylic acid in 100 ml of reagent grade acetone was added 6.91 g (0.05 mole) of anhydrous potassium carbonate. To this stirred mixture was added 10.26 g (0.06 mole) of benzyl bromide diluted with a small volume of acetone. The reaction mixture was stirred overnight at room temperature and filtered with suction. The insoluble material was washed on the filter with additional acetone. The acetone wash solutions and the filtrate were combined and evaporated in vacuo to dryness. The resulting product residue was dissolved in 200 ml of diethyl ether and washed twice with water, once with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether solvent provided a straw-colored semi-viscous liquid which distilled at 145°-146° C./3 mm (5.31 g) identified as the title product.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([N:10]=O)[CH:6]=[N:5]1.[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>O.CO.[Pd]>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[F:1][CH2:2][CH2:3][N:4]1[C:8]([NH2:9])=[C:7]([NH2:10])[CH:6]=[N:5]1
Reactant: Nc1c(N=O)cnn1CCF
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: Nc1cnn(CCF)c1N
Reaction time: 7.5 h
Yield: 95.2 %

Procedure:
To a solution of 1-(2-fluoroethyl)-4-nitroso-1H-pyrazol-5-amine (4.8 g) in water (30 ml) and methanol (30 ml) were added sulfuric acid (2.98 g) and 10% palladium on carbon (2.5 g), and the mixture was hydrogenated under balloon pressure for 7.5 hours. The reaction mixture was filtered through a bed of Celite, and the filtrate was concentrated in vacuo. 2-Propanol was added to the residue, and the precipitate was collected by filtration to give 1-(2-fluoroethyl)-1H-pyrazole-4,5-diamine sulfate (7 g).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:16][C:13]1([CH3:17])[CH2:14][O:15][CH:10]([CH2:9][OH:8])[O:11][CH2:12]1
Reactant: CC1(C)COC(COCc2ccccc2)OC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1(C)COC(CO)OC1
Yield: 85 %

Procedure:
The 2-((benzyloxy)methyl)-5,5-dimethyl-1,3-dioxane (7.6 g, 32.2 mmol) obtained by the step (1a) was mixed with 20% palladium hydroxide (700 mg) and ethyl acetate (70 ml). The mixture was stirred in a hydrogen atmosphere overnight. The reaction mixture was allowed to stand for further 5 days in the same hydrogen atmosphere. The reaction vessel was purged with nitrogen, the catalyst was filtered off, and the solvent was distilled off to obtain the title compound (4 g, yield: 85%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:27]([C:36]4[CH:41]=[CH:40][C:39]([NH:42][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5C(OC(C)(C)C)=O)=[O:44])=[CH:38][CH:37]=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[N:17]=1)=O)(C)(C)C.[ClH:57]>O1CCOCC1>[ClH:57].[F:35][C:32]1[CH:33]=[CH:34][C:29]([N:28]2[CH:24]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[N:17]=[C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)[NH:14][CH:15]=4)=[CH:23][CH:22]=3)[CH2:25][CH2:26][CH:27]2[C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43]([C@@H:45]3[CH2:49][CH2:48][CH2:47][NH:46]3)=[O:44])=[CH:38][CH:37]=2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(C2CCC(c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)N2c2ccc(F)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(C2CCC(c3ccc(-c4c[nH]c([C@@H]5CCCN5)n4)cc3)N2c2ccc(F)cc2)cc1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolved the product from Example 39H (350 mg, 0.458 mmol) in 4M hydrochloric acid in dioxane solution (6 mL) and stirred the solution at room temperature for 30 min then concentrated the mixture under high vacuum to a solid (approx. 310 mg) as a hydrochloride salt that was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Br:14][C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([N:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[Br:14])=[O:6]
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: Brc1ccc[nH]1
Product: COc1ccc(C(=O)n2cccc2Br)c(OC)c1
Yield: 299.4 %

Procedure:
Following the procedure of Example B, 2,4-dimethoxybenzoyl chloride (6.74 g, 3.36 mmol) and 2-bromopyrrole (22.4 mmol) gave 3.12 g of the title compound: mp 81-82° C.; 1H NMR (CDCl3) δ: 7.42 (1 H, t, J=8.4), 6.99 (1 H, t, J=1.8), 6.70-6.45 (2 H, m), 6.42-6.25 (1 H, m), 6.16 (1 H, t, J=3.5), 3.87 (3 H, s), 3.77 (3 H, s).