Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6]2=[CH:8][S:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][CH:13]=1.[H-].[Na+].[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34]Br)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>CN(C)C=O>[O:11]=[C:4]1[N:3]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[CH:16][CH:17]=2)[C:2]([S:1][CH2:34][CH2:33][NH:32][C:31](=[O:36])[O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:7][C:6]2=[CH:8][S:9][CH:10]=[C:5]12
Reactant: O=c1c2cscc2[nH]c(=S)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
2-Thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydrothieno[3,4-d]pyrimidin-4(1H)-one (1.59 g) was dissolved in N,N-dimethylformamide (20 ml), sodium hydride (60% in oil, 0.25 g) and tert-butyl(2-bromoethyl)carbamate (1.49 g) were added successively thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was poured into saturated aqueous ammonium chloride solution (30 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (2.12 g) as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:12]([NH2:13])=[C:11]([NH2:14])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[C:15](O)(=[O:17])[CH3:16]>>[CH2:1]([N:5]1[C:12]([NH2:13])=[C:11]([NH:14][C:15](=[O:17])[CH3:16])[C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(N)c(N)c(=O)[nH]c1=O
Reactant: CC(=O)O
Product: CCCCn1c(N)c(NC(C)=O)c(=O)[nH]c1=O

Procedure:
59.4 g (0.3 mole) of 1-butyl-5,6-diaminouracil are refluxed for 2 hours with stirring in 240 ml of acetic acid in a reactor equipped with a condenser. The acetic acid is evaporated and the residue is taken up in a little ethanol which is then evaporated. This operation is repeated until a semi-crystalline residue is obtained. The semi-crystalline residue thus obtained is then triturated until solidification is complete. The solid is filtered and washed with ether, giving 72 g of fine, faintly yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1.[CH:17]([N-]C(C)C)(C)C.[Li+].CI>>[F:1][C:2]1[C:7]([CH3:17])=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC1(C)COC(c2cc(F)c(F)cc2F)=N1
Agent: [Li+]
Solvent: CI
Product: Cc1c(F)c(F)cc(C2=NC(C)(C)CO2)c1F

Procedure:
The 2-(2,4,5-trifluorophenyl)-4, 4-dimethyl-2-oxazoline was also treated with lithium diisopropylamide followed by methyl iodide to give 2-(2,4,5-trifluoro-3-methylphenyl)-4,4-dimethyl-2-oxazoline. This intermediate was, in turn, treated with lithium diisopropylamide, then with methyl iodide, to give 2-(2,4,5-trifluoro-3,6-dimethylphenyl)-4,4-dimethyl-2-oxazoline. Hydrolysis of the oxazoline gave 2,4,5-trifluoro-3,6-dimethylbenzoic acid, which was elaborated into 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5,8-dimethyl-4-oxo-3-quinolinecarboxylic acid in the usual manner.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19](O)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][C:30]12[CH2:37][CH:34]([NH:35][CH2:36]1)[CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:35]3[CH2:36][C:30]4([CH3:29])[CH2:37][CH:34]3[CH2:33][C:32]([CH3:39])([CH3:38])[CH2:31]4)=[O:20])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)O)cs2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)CC2CC(C)(CN2C(=O)c2csc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
4-(4-Carboxy-thiophen-2-yl)-piperidine-1-carboxylic acid t-butyl ester (0.1 g, 0.32 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.96 mmol), 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.35 mmol) and HATU (0.35 mmol) were added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by flash chromatography, eluting with 0-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.132 g). 1H NMR (400 MHz, CHCl3-d; 80° C.); □ 7.6 (s, 1H), 7.0 (s, 1H), 4.3 (m, 1H), 4.0 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 3.0 (m, 1H), 2.9 (m, 1.9 (m, 2H), 1.7 (m, 1H), 1.6-0.9 (m, 26H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-])=O>[Pd].C(O)C>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:12]=[CH:11][C:7]1=2
Reactant: O=[N+]([O-])c1ccc2sccc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2sccc2c1
Yield: 101.3 %

Procedure:
A mixture of 5-nitrobenzo[b]thiophene (3.09 g, 17.0 mmol) and 10% palladium on carbon (Aldrich, cat. No. 20, 569-9) (150 mg) in ethanol (90 mL) was shaken in a Parr flask under a hydrogen atmosphere of 3 bar. After 16 h the catalyst was filtered off over a celite pad and washed with ethanol (2×30 mL). The filtrate was evaporated in vacuo to yield benzo[b]thiophen-5-amine (2.57 g, 100%) as a dark purple amorphous solid. 1H NMR δ (CDCl3, 400 MHz) 3.70 (br. s., 2 H), 6.78 (dd, J=8.61, 1.96 Hz, 1 H), 7.10 (d, J=2.35 Hz, 1 H), 7.14 (d, J=5.09 Hz, 1 H), 7.38 (d, J=5.48 Hz, 1 H), 7.63 (d, J=8.61 Hz, 1 H).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:21])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(Cl)Cl.C(OCC)(=O)C>[O:21]=[C:9]1[NH:8][C:12]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=2[N:10]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)n(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.6 %

Procedure:
Part 1. To a chilled solution of methyl 1-[(tert-butyl)oxycarbonyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (0.37 g, 1.28 mmol) in CH2Cl2 (8 mL) and N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) was added a solution of benzyl chloroformate (0.208 mL, 1.46 mmol) in CH2Cl2 (2 mL). The reaction was stirred at room temperature for 2.5 hr, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. This residue was dissolved in CH2Cl2 (9 mL) and treated with neat trifluoroacetic acid (2 mL) at 0° C. for 40 min, diluted with ethyl acetate, washed with 5% NaHCO3, water and brine, dried over sodium sulfate and concentrated to yield methyl 2-oxo-3-[benzyloxycarbonyl]-(3H)—benzimidazole-5-carboxylate (0.37 g, 89%) as an off-white solid. 1H NMR (CDCl3) δ: 3.51 (s, 3H); 5.14 (s, 2H); 6.67-6.69 (d, 1H); 6.97-7.06 (m, 5H); 7.17-7.18 (d, 1H); 7.51-7.53 (d, 1H); 8.07 (s, 1H). ES-MS (M+Na)+=349.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][NH:18][C:19]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2.S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2
Reactant: COC(=O)c1cc2nc(Cl)c(NNC(=O)C3CCOCC3)nc2cc1C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc2nc(Cl)c3nnc(C4CCOCC4)n3c2cc1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 12.7 g of methyl 3-chloro-7-methyl-2-[2-(tetrahydro-2H-pyran-4-ylcarbonyl)hydrazino]quinoxaline-6-carboxylate and 250 mL of tetrahydrofuran was added 5 mL of thionyl chloride, followed by stirring at 70° C. overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure and the obtained solid was washed with diethyl ether to obtain 10.4 g of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1>CS(C)=O>[CH3:1][C:2]1[N:6]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(OC(F)(F)F)cc4)no3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (31 mg, 0.1 mmol) in DMSO (0.5 mL), Cs2CO3 (65 mg, 0.2 mmol) and α-bromo-p-xylene (20 mg, 0.11 mmol) were added at RT. The mixture was stirred at RT overnight. The resulting crude product was purified by pre-HPLC (Mobile phase: A=0.01% TFA/H2O, B=0.01% TFA/MeCN; Gradient: B=50%-90% in 12 min; Column: C18) and lyophilized to give 5-(5-methyl-1-(4-methylbenzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (20 mg, 48%). MS (ES+) C20H16F3N5O2 requires: 415. found: 416 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 8.22 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 5.52 (s, 2H), 2.57 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].C(O[C:19]1(OCC)[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])C>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5](=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH3:24])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:15])[CH3:2]
Reactant: CCOC1(OCC)CCCN1C
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=C1CCCN1C)c1ccc([N+](=O)[O-])cc1

Procedure:
Boil 50 g of 4-nitrophenylacetic acid ethyl ester and 41.4 g of 2,2-diethoxy-1-methylpyrrolidine under reflux for 3 hours in 250 ml of benzene. Distil off the benzene before recrystallizing the resulting residue from diethyl ether/petroleum ether to obtain the title compound at a yield of 52.6 g (77% of theory) in the form of red crystals of m.p. 82° to 83°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][CH:9]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc(-c2ccccc2F)nc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCOc1ccc(-c2ccccc2F)nc1

Procedure:
189 mg (0.52 mmol) of (2-(2-(6-(2-fluorophenyl)pyridin-3-yloxy)ethyl)isoindole-1,3-dione and 236 mg (4.72 mmol) of hydrazine hydrate (24%) were stirred in 10 ml of ethanol under reflux for 7 h. After cooling the residue was filtered, washed and dried. Yield: 165 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12](O)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][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][OH:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccc(Br)cc12
Yield: 64.6 %

Procedure:
To a stirred solution of 5-bromoindole-3-acetic acid (1.9 g., 7.48 mmol., 1 eq.) in dry THF (17 mL.) at 0° C. was added lithium aluminum hydride (570 mg. 14.96 mmol., 2 eq.) portionwise over 30 minutes. The reaction mixture coagulated. THF (20 mL.) was added and the cooling bath was removed. The mixture was stirred vigorously. Let stir overnight. The reaction mixture was carefully quenched with 1N aqueous HC1 and then acidified with 2N aqueous HC1. The mixture was filtered through Celite™ and the Celite™ was washed with THF. The filtrate was concentrated in vacuo, dissolved in EtOAc, and washed with water. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. TLC analysis of the residue showed unreacted starting material. The residue was dissolved in Et2O and extracted with 0.25N aqueous NaOH. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo giving 1.16 g 5-bromo-3-hydroxyethylindole.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:22][CH:21]=2)[C:12]2[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8].CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH2:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])=[CH:24][CH:25]=2)[C:12]2[C:13](=[O:17])[N:14]([CH2:2][C:3]#[N:4])[CH:15]=[CH:16][C:11]=2[N:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: N#CCCl
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccn(CC#N)c(=O)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.79 g of chloroacetonitrile in 5 ml of DMF is added dropwise at 20°, with stirring, to a solution of 3.82 g of 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine and 1.17 g of potassium tert-butylate in 20 ml of DMF. The mixture is stirred at 20° for a further 30 min and poured on to ice, hydrochloric acid is added to pH 6 and the mixture is worked up in conventional manner to give 2-butyl-3-(2'-cyanobiphenyl-4-ylmethyl)-5-cyanomethyl-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine , m.p. 64°.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:11])[CH3:10])[C:4]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:3]1=2>CO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:11])[CH3:10])[C:4]=2[CH:12]=1
Reactant: CC(=O)N1CCCC(C)(C)c2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCCC(C)(C)c2ccc(N)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone (1.05 g, 40 mmol) and 10% Pd—C (0.2 g) in MeOH (20 mL) was stirred under H2 (1 atm) at room temperature for 4 h. After filtration, the filtrate was concentrated to give 1-(8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[b]azepin-1-yl)ethanone as a white solid (DC-4) (880 mg, 94%). 1H NMR (CDCl3) δ 7.06 (d, J=8.0 Hz, 1H), 6.59 (dd, J=8.4, 2.4 Hz, 1H), 6.50 (br s, 1H), 4.18-4.05 (m, 1H), 3.46-3.36 (m, 1H), 2.23 (s, 3H), 1.92-1.85 (m, 1H), 1.61-1.51 (m, 3H), 1.21 (s, 3H), 0.73 (t, J=7.2 Hz, 3H); ESI-MS 233.0 m/z (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.FC(F)(F)S(O[CH2:23][CH:24]([F:34])[CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])(=O)=O>CN(C=O)C.C(OCC)C>[Si:27]([O:26][CH2:25][CH:24]([F:34])[CH2:23][N:14]1[CH:15]=[C:11]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]2)[CH:12]=[N:13]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCC(F)COS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC(F)CO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (0.247 g, 6.17 mmol) was suspended in 10 mL of DMF. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.958 g, 4.94 mmol) was added in 5 mL of DMF dropwise via syringe and the mixture was stirred at room temperature for 30 minutes. Then 3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoropropyl trifluoromethanesulfonate (1.40 g, 4.11 mmol) was added in 5 mL of DMF dropwise via syringe. After 20 minutes, the reaction mixture was diluted in diethyl ether, washed with water (3×50 mL) and brine then dried over magnesium sulfate, filtered and concentrated to afford 1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoropropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:10]=1)[C:5]([OH:7])=[O:6].Br[C:17]1C=C(C=C(O)C=1)C(OC)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: COC(=O)c1cc(O)cc(Br)c1
Reactant: O=C(O)c1cc(Br)cc(OC(F)(F)F)c1
Product: COC(=O)c1cc(Br)cc(OC(F)(F)F)c1

Procedure:
Prepared from 3-bromo-5-(trifluoromethoxy)benzoic acid according to the procedure for methyl 3-bromo-5-hydroxybenzoate. LCMS-ESI (m/z) calculated for C9H6BrF3O3: 299.0; no m/z observed, tR=4.08 min. 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J=3.9, 2.4 Hz, 1H), 7.83 (dt, J=2.2, 1.2 Hz, 1H), 7.57 (ddd, J=2.4, 1.8, 0.9 Hz, 1H), 3.99-3.87 (m, 3H).
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22](=[O:34])([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[O:23][CH:24](Cl)[CH3:25]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH:24]([O:23][C:22]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:34])[CH3:25])=[O:19]
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Product: CC(OC(=O)OC1CCCCC1)OC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 1.35 g) and 1-chloroethyl cyclohexyl carbonate (2.06 mL) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-10, 113 mg) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:14][NH2:15])[CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl.[C:17](=N)(OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N)(=N)C1C=CC=CC=1>CO.O=[Mn]=O>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]3[C:10](=[CH:12][CH:13]=2)[N:11]=[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]=[CH:14]3)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(N)c(CN)c1
Reactant: COC(=N)c1ccccc1
Agent: O=[Mn]=O
Agent: Cl
Agent: N=C(N)c1ccccc1
Solvent: CO
Product: Cc1nccn1-c1ccc2nc(-c3ccccc3)ncc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
4-(2-methyl-1H-imidazol-1-yl)-2-aminomethylaniline (2.0 g, 10 mmol) and methyl benzimidate hydrochloride (3.5 g, 20 mmol; RN: 5873-90-5, Aldrich) were dissolved in methanol (50 mL), the resulting mixture was heated at reflux for 2 hours, during this time the aminomethyl-derivative was converted into the corresponding benzamidine. After that, the methanol was evaporated and the residue taken up with glacial acetic acid (50 mL), the reaction mixture was heated at reflux for 1.5 hours. After cooling at r.t. the reaction mixture was diluted with toluene (50 mL) and evaporated. The residue was taken up with AcOEt (400 mL), washed with aq. ammonia, with water, then dried and concentrated. The obtained oily residue was dissolved in DCM (400 mL) and MnO2 (6.0 g, 70 mmol) was added at r.t., in three portions, over 2 hours. The resulting suspension was stirred at r.t. for 24 hrs, then filtered over celite and the cake was rinsed with DCM. The combined filtrate and washings were concentrated and the residue chromatographed over silica gel (DCM/MeOH/NH3, 85:25.2) the appropriate combined fractions were evaporated and the residue taken up with ethyl ether, heated at reflux for 5 minutes then cooled at 25° C. to crystallize the titled product as slightly brown powder (2.0 g; yield: 74%). C18H14N4, MW: 286.34; MS: m/z 287 (M+H); 1H-NMR (200 MHz, d6-DMSO) ppm: 2.40 (s, 1H), 7.0 (s, 1H), 7.40 (s, 1H), 7.60 (m, 3H), 8.10-8.30 (m, 3H), 8.60 (m, 2H), 9.80 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][CH:14]1[CH2:20][N:19]([CH2:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[CH2:18][CH2:17][N:16]([CH3:30])[CH2:15]1>CN(C)C=O>[CH3:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[CH2:21][N:19]1[CH2:20][CH:14]([NH:13][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:15][N:16]([CH3:30])[CH2:17][CH2:18]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Cc1ccc(C)c(CN2CCN(C)CC(N)C2)c1
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(CN2CCN(C)CC(NC(=O)c3n[nH]c4ccccc34)C2)c1
Temperature: 60 °C
Yield: 67.4 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (1.0 g) in N,N-dimethylformamide (20 ml), N,N'-carbonyldiimidazole (1.1 g) is added, and the mixture is heated at 60° C. for 2 hours. 6-Amino-1-(2,5-dimethylbenzyl)-4-methylhexahydro-1H-1,4-diazepine (1.5 g) is added to the reaction mixture, and the mixture is heated at 60° C. for 2 hours. The solvent is evaporated under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with water and aqueous sodium hydroxide solution, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (1.6 g) as an oil. The free base thus obtained is converted to the fumarate of the title compound in a usual manner, m.p. 168°-170° C. (recrystallized from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](SCCC)=[N:8][C:7]=2[N:29]=1.[O-:30][CH2:31][CH3:32].[Na+].Cl>C(O)C>[CH2:31]([O:30][C:9]1[N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:29][C:7]=2[N:8]=1)[CH3:32]
Reactant: CC[O-]
Reactant: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
7-Methoxy-2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (200 mg) was dissolved in ethanol (15 ml), sodium ethoxide (20% ethanol solution, 850 mg) was added thereto, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into 0.2M hydrochloric acid (15 ml), and the precipitated precipitate was collected by filtration, and dissolved in tetrahydrofuran (15 ml). The solution was diluted with ethyl acetate (30 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (95 mg).