Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[SH-].[Na+].[S:30](=O)(=O)(O)O>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:10])[SH:30])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [SH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Three grams (14.1 mmol) of 2-(4-chlorophenyl)-3-methylbutanoic acid is dissolved in approximately 50 ml of dry dimethylformamide, after which 1.43 g (14.1 mmol) of triethylamine is added in one portion. The solution is cooled to 0° and 1.59 g (14.1 mmol) of ethyl chloroformate is slowly added over 30 seconds. After 0.5 hour 3.15 g (28.2 mmol) of sodium hydrosulfide is added. The mixture is stirred overnight at room temperature. The reaction mixture is then poured into 150 ml of water and adjusted to pH 3 with 5% aqueous sulfuric acid. Extraction with 50 ml methylene chloride (3×) is followed by drying and stripping. Dimethylforamide is still present, so the product is taken up in ether and washed with 200 ml of water, dried and stripped to yield 2-(4-chlorophenyl)-3-methylbutanethioic S-acid.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:29][NH:30][CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:27][CH3:28])=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[C:13]3[CH:14]=[N:15][C:16]([O:33][CH2:32][CH2:31][NH:30][CH3:29])=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CNCCO
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccc2oc(Cl)cc2c1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)nc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 16, step C described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(6-chloropyridin-3-yl)but-1-enyl)phenol (70 mg, 1.0 eq) was reacted with 2-(methylamino)ethanol (128 mg, 10 eq) to give the desired product (Z/E=1/1). m/z=449[M+1]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:22]C)=[O:21])[C:3]=1[CH3:29].[NH:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][C:31]1=[O:39].C([O-])([O-])=O.[K+].[K+].[F-].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO.C1COCC1.CC(O)=O.C1(C)C=CC=CC=1>[C:25]([O:24][CH:19]([C:4]1[C:3]([CH3:29])=[C:2]([C:34]2[CH:35]=[N:30][C:31](=[O:39])[NH:32][CH:33]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:26])[CH3:28]
Reactant: O=c1ncc(B(O)O)c[nH]1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1cnc(=O)[nH]c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
A suspension methyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (10.5 mg, 22.1 μmol), [1H]pyrimidin-2-one-5-yl-boronic acid (25 mg, 0.11 mmol), PdCl2(dppf) (3.2 mg, 4.4 μmol), K2CO3 (46 mg, 0.33 mmol), PhMe (500 μL), EtOH (absolute, 250 μL), and H2O (250 μL) was heated to 100° C. for 30 min, but conversion was poor. The reaction was treated with glacial AcOH (60 μL, 1.05 mmol) and KF (40 mg, 0.688 mmol). More PdCl2(dppf) (3.2 mg, 4.4 μmol) and [1H]pyrimidin-2-one-5-yl-boronic acid (7 mg, 30 μmol) were added and the reaction was heated to 100° C. After 2 h, the reaction was added to H2O (15 mL) and glacial AcOH (0.2 mL). The system was extracted with EtOAc (3×10 mL). Combined organic phases were dried (Na2SO4), filtered, and concentrated. The crude material was treated with THF (750 μL), EtOH (absolute, 750 μL), H2O (500 μL), and LiOH monohydrate (50 mg 1.2 mmol). The suspension was heated to 100° C. for 30 min. The reaction was cooled to 23° C., filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) (3.8 mg, 36% over 2 steps). 1H-NMR: (400 MHz, DMSO-d6): δ 12.8 (s, broad, 1H), 8.29 (app. s, broad, 1H), 7.75-7.68 (m, 2H), 7.58-7.44 (m, 4H), 7.43-7.38 (m, 2H), 7.25 (d, J=8.2 Hz, 1H), 5.12 (s, 1H), 2.38 (s, 3H), 0.96 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26ClN2O4: 477.2; Found: 477.2.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].[I-].[K+].[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38]Cl)[N:37]=1)(=[O:31])[CH3:30]>>[C:29]([NH:32][C:33]1[S:34][CH:35]=[C:36]([CH2:38][O:22][C:16]2[CH:15]=[C:14]3[C:19]([C:10]([NH:9][C:8]4[CH:23]=[CH:24][C:25]([CH3:26])=[C:6]([O:5][C:2](=[O:4])[CH3:3])[CH:7]=4)=[N:11][CH:12]=[N:13]3)=[CH:18][C:17]=2[O:20][CH3:21])[N:37]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1csc(NC(C)=O)n1
Yield: 41.9 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of catalytic potassium iodide with 2-acetamido-4-chloromethylthiazole (252 mg) to give 7-(2-acetamidothiazol-4-ylmethoxy)-4-(3-acetoxy-4-methylanilino)-6-methoxyquinazoline (220 mg, 42%).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[C:9][Br:10])=[C:6]([N:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:5]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][C:27]=2[Cl:37])[N:4]=1)#[N:2].FC(F)(F)C(O)=O.CCOCC.C(=O)([O-])O.[Na+]>ClCCl>[C:15]([O:14][C:12]([NH:11][C:6]1[N:5]([C:26]2[C:31]([Cl:32])=[CH:30][C:29]([C:33]([F:34])([F:35])[F:36])=[CH:28][C:27]=2[Cl:37])[N:4]=[C:3]([C:1]#[N:2])[C:7]=1[C:8]#[C:9][Br:10])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(C#CBr)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1c(C#CBr)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
To a solution of 3-cyano-5-di-(t-butoxycarbonyl)amino-1-(2,6-dichloro-4-trifluoromethylphenyl)4bromoethynylpyrazole (200 mg, the compound of Example B5) in anhydrous dichloromethane (2 ml) was added dropwise trifluoroacetic acid (0.2 ml). After 30 minutes the reaction mixture was treated with ether (10 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml). The organic layer was separated, dried (MgSO4) and evaporated to provide the title compound as a white solid m.p. 168-70° C.
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[CH:14]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:7][CH:8]=2)=[O:2].[BH4-].[Na+].C(O)(=O)C>CO.O>[OH:2][CH2:1][CH:3]1[C:15]2[CH:14]=[C:13]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:7][CH:8]=2
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(C=O)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(CO)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9-Formyl-2,7-di(Boc-amino)fluorene (0.47 g, 1.1 mmol) was dissolved in anhydrous methanol (MeOH) (5 mL) under an argon atmosphere. NaBH4 (1.2 eq, 1.3 mmol, 0.05 g) was added and the reaction was stirred at room temperature for five hours. The reaction was diluted with deionized water and acidified to pH 5 with glacial acetic acid. The reaction was extracted with ethyl acetate (2×100 mL) and the organic layers were washed with saturated NaHCO3 (4×20 mL) and brine (3×20 mL). The organic layers were dried over MgSO4, filtered and evaporated. The crude product, orange solid, was purified by flash chromatography: silica gel 60 Å gradient elution 1-5% methanol in chloroform (alternative gradient elution with 15-20% ethyl acetate in dichloromethane). Product was a yellow solid (0.39, 83%). 1H-NMR (CD3OD): δ (ppm) 7.9 (s, 0.5H, NH urethane); 7.7 (s, 2H, Ar); 7.6 (d, 2H, Ar); 7.4 (d, 2H, Ar); 4.0 (m, 1H, CH); 3.9 (m, 2H, CH2); 1.6 (s, 18H, Boc).
Reaction SMILES: CC(C)([O-])C.[K+].[N+]([O-])(O)=O.[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18](=[NH:20])[NH2:19])[N:13]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]=[S:23]>CS(C)=O>[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18]([NH:19][C:22]([NH:21][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[S:23])=[NH:20])[N:13]=1
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CS(C)=O
Product: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
554.7 mg (4.94 mmol) of potassium tert-butoxide are dissolved in 12 ml of DMSO while cooling slightly in ice, and then 596.8 mg (2.96 mmol) of 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate are added. A clear solution is produced after stirring for about 5 minutes. Then 500 mg (2.47 mmol) of tert-butyl (2-isothiocyanatoethyl)carbamate are added, and the icebath is removed. The mixture is heated at 60° C. for a further 3 h and the solution obtained in this way is employed for the further subsequent reactions.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]=2)[O:7][C:6]=1[C:29](O)=[O:30])(=[O:3])[CH3:2].Cl.[CH:33]12[CH2:40][CH2:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34]2.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:33]12[CH2:40][CH2:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][N:34]2[C:29]([C:6]1[O:7][C:8]2=[N:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]=[C:13]2[C:5]=1[NH:4][C:1](=[O:3])[CH3:2])=[O:30]
Reactant: CC(=O)Nc1c(C(=O)O)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: C1CC2CCC1CN2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)Nc1c(C(=O)N2CC3CCC2CC3)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.027 g (0.0568 mmol) of the product from Step A in CH2Cl2 (0.6 mL) was treated with 2-azabicyclo[2.2.2]octane hydrochloride (0.009 g; 0.0625 mmol), EDC (0.016 g; 0.0852 mmol), DMAP (0.007 g; 0.0568 mmol), and 1-methylmorpholine (19 μL; 0.170 mmol), then stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 568.0 (M+1), 570.0 (M+3); Rt=4.68 min.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I[CH3:18]>O1CCCC1.O>[CH3:18][O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.19 g, 60% in mineral oil, 29.7 mmol) was added portionwise to a cooled (10° C.) solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (Bioorg. Med. Chem. Lett. 10; 24; 2000; 2815) in tetrahydrofuran (80 mL), and the suspension stirred at room temperature for 1 hour. Iodomethane (1.85 mL, 29.7 mmol) was added, and the reaction stirred at 50° C. for 20 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (2×150 mL) and the combined organic extracts washed with saturated sodium bicarbonate solution (50 mL), dried (MgSO4) and evaporated under reduced pressure, to afford the title compound as a golden oil, 5.24 g.
Reaction SMILES: [CH:1]([CH:4]([C:10]([O:12]CC)=O)[C:5]([O:7]CC)=O)([CH3:3])[CH3:2].C[O-].[Na+].[NH2:18][C:19]([NH2:21])=[O:20]>CO>[CH3:3][CH:1]([CH:4]1[C:5](=[O:7])[NH:21][C:19](=[O:20])[NH:18][C:10]1=[O:12])[CH3:2]
Reactant: NC(N)=O
Reactant: CCOC(=O)C(C(=O)OCC)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C1C(=O)NC(=O)NC1=O
Temperature: 20 °C
Yield: 69.7 %

Procedure:
456 g (2.25 mol) of diethyl isopropylmalonate, 650 ml of a 30% methanolic sodium methoxide solution and 910 ml of methanol are charged to a 2 liter reactor equipped with an anchor stirrer. The mixture is brought to reflux for thirty minutes before adding 135 g (2.25 mol) of urea in the solid form while maintaining the reflux. The reaction mixture at the end of the reaction is a thick white suspension which is brought to dryness by evaporation of the methanol under vacuum. The residue is taken up in 1370 ml of water and then filtered after cooling to 20° C. The filtrate is treated by addition of the amount of hydrochloric acid needed to bring the pH to 2-3, and the precipitate obtained is filtered off under cold conditions and washed with ice-cold water in order to obtain 267 g of 5-(1-methylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:12][CH:11]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)cc3)c(C)c2)cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)O)cc3)c(C)c2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.175 mL, 0.175 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 49-(1); 30.1 mg, 0.058 mmol) in methanol-tetrahydrofuran (1:1, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (25.2 mg, 87%).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[C:4]([OH:10])[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C=O>[CH2:22]([O:10][C:4]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:2]([Br:1])[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(O)nn(C(C)C)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)nn(C(C)C)c1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ethyl 5-bromo-3-hydroxy-1-isopropylpyrazole-4-carboxylate (5.8 g) and potassium carbonate (3.5 g) were suspended in N,N-dimethylformamide (50 mL) and to the stirred suspension was added benzyl bromide (2.76 mL) under ice cooling. The mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid (100 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give 7.7 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][CH:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]([CH3:3])[C:4]([O:6][CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7])[CH3:19])=[O:5]
Reactant: CC(N)C(=O)O
Reactant: CCCCCCCCCCCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(C)OC(=O)C(C)N
Yield: 87.4 %

Procedure:
To a stirred solution of DL-alanine 1 (15 g, 168.5 mmol) in toluene (300 mL) was added 2-tridecanol 68 (30.3 g, 151.68 mmol) in one lot, followed by pTSA (35.26 g, 185.38 mmol). After the addition, the temperature of the reaction mixture was slowly raised to reflux temperature, the water was separated azeotropically and the reaction mixture was monitored by TLC. The reaction mixture was concentrated under vacuum, the obtained residue was taken in ethyl acetate (200 mL) and washed with aqueous 5% Na2CO3 (3×50 mL) followed by brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford 69 (36 g, yield: 78.9%) as a liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.Cl[C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[C:26]([Cl:33])[C:22]=1[C:23]([OH:25])=[O:24]>ClCCl>[Cl:33][C:26]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=2)[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CN(C)c1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 41.0 g of N,N-dimethyl-p-phenylenediamine, 100 ml of N,N-dimethylaniline, and 23.6 g of 2,6-dichloro-3-nitrobenzoic acid was heated for seven hours on a steam bath. The resulting cake was suspended in dichloromethane, filtered, and the solid washed with water. Recrystallization from DMF-ethanol provided 6-chloro-2[[4-(dimethylamino)phenyl]amino]3-nitrobenzoic acid, mp 222°-223° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([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)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)=[O:9])=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Yield: 93 %

Procedure:
A solution of tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (1.00 g, 3.00 mmol) in MeOH (60 ml) was hydrogenated at 20° C. at atmospheric pressure using an H-Cube (flow rate at 1 ml/min and full hydrogen mode) using a Pd/C cartridge. The solvent was removed in vacuo to afford tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (0.85 g, 2.79 mmol, 93%) as a white solid. 1H NMR (CDCl3) δ 1.41 (9H, s), 3.38 (4H, m), 3.53 (4H, m), 4.07 (2H, br. s), 6.55 (2H, d), 7.17 (2H, d). LCMS (2) Rt: 2.14 min; m/z (ES+) 306.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[CH3:31][N:32]([CH2:34][CH2:35]Cl)[CH3:33]>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: CN(C)CCCl
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN(C)C)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(N,N-dimethylamino)ethyl chloride essentially as previously described. mp 152° C., NMR, IR, MS 539, 541.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([NH2:24])[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1>O.CN(C=O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:24][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2N)C1

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (17.45 mmol, 4.0 g) and benzene-1,2-diamine (17.45 mmol, 1.87 g) were added to a 100 mL round-bottomed flask equipped for stirring under nitrogen. DMF (30 mL) and 4-methylmorpholine (52.35 mmol, 5.76 mL) were added and the resultant solution was allowed to stir for 5 min at room temperature. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (20.94 mmol, 4.01 g) and 1H-benzo[d][1,2,3]triazol-1-ol (20.94 mmol, 2.83 g) were then added and the reaction was allowed to stir at room temperature for 16 hr. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed three times with water, two times with saturated aqueous sodium bicarbonate, and once with saturated aqueous sodium chloride. The organic layer was collected and dried with Na2SO4. This mixture was then filtered, the filtrate was collected and concentrated and dried in-vacuo affording (R)-tert-Butyl 3-(2-aminophenylcarbamoyl)piperidine-1-carboxylate (7A) as a brownish foam that was carried directly on to the next step without further purification. ESI-MS: m/z 320.4 (M+H)+.