Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]S(O)(=O)=O.[C:6]([O:10][C:11](=[O:27])[N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][CH2:24][OH:25])[CH:20]=[CH:19][C:18]=1[Cl:26])[CH:13]1[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>O.CC(C)=O>[C:6]([O:10][C:11]([N:12]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]([OH:1])=[O:25])[CH:20]=[CH:19][C:18]=1[Cl:26])[CH:13]1[CH2:14][CH2:15]1)=[O:27])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCO)ccc1Cl)C1CC1
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Conc. H2SO4 (98%, 5.80 mL) was carefully added to a suspension of CrO3 (6.70 g, 67.0 mmol) in water (12.5 mL). Water was slowly added up to a total volume of 22.5 mL, at which stage the mixture was a clear sol. This sol. was added dropwise to a sol. of [2-chloro-5-(2-hydroxy-ethyl)-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (13.0 g, 39.9 mmol) in acetone (140 mL) at 0° C. When the addition was complete, the mixture was stirred at 0° C. for 30 min. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with aq. 1M HCl. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (12.2 g, 90%) that was used further without purification. LC-MS: tR=0.95 min; ES+: 325.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[CH2:16][C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:23])[CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:11])=[S:10])[S:20][CH:21]=1)[CH3:13]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: CCOC(=O)Cc1csc(NC(=S)Nc2cc(Cl)ccc2C)n1
Yield: 39.9 %

Procedure:
Prepared using Method B from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 4.56 g (24.5 mmol) of 2-(2-amino-thiazol-4-yl)-acetic acid ethyl ester to give 3.62 g of title compound as a white solid (40% yield, m.p. 177-179° C.).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=1.[BH4-].[Na+].CCOCC>C(O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([CH2:14][CH2:15][CH:16]([OH:18])[CH3:17])[CH:3]=1
Reactant: COc1ccc2cc(CCC(C)=O)cc(F)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc2cc(CCC(C)O)cc(F)c2c1

Procedure:
4-(4-Fluoro-6-methoxy-2-naphthyl)butan-2-one (14.1 g) was dissolved in ethanol (200 ml) and sodium borohydride (6.7 g) was added to the stirred solution. After 1 hour ether (600 ml) was added and the solution was washed twice with brine, then with dilute hydrochloric acid and sodium hydrogen carbonate solution. After drying over anhydrous sodium sulphate the solvent was removed under reduced pressure. The oil obtained was chromatographed on silica gel (700 g) using an elution gradient from benzene to ether. The desired product was obtained as an oil. This was triturated with 60-80 petroleum ether to give the title compound as pale yellow crystals (5.65 g., 40%; m.p. 58°-60°).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH:17]([N:20]=[C:21]=[O:22])([CH3:19])[CH3:18]>O1CCCC1>[CH:17]([NH:20][C:21](=[O:22])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])([CH3:19])[CH3:18]
Reactant: CC(C)N=C=O
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCOC1
Product: CC(C)NC(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Isopropyl isocyanate (34 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was purified by silica gel chromatography (1-3% gradient, 2M ammonia in methanol:methylene chloride). The solvent was evaporated to give 21.8 mg (63%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[C:2]1([NH:1][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Nc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Nc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a solution of 1-aminonaphthalene (1.43 g, 10 mmol) and triethylamine (1.5 mL, 10.8 mmol) in dimethylformamide (3.0 mL) at room temperature under nitrogen was added ethyl 2-bromopropionate (1.4 mL, 10.8 mmol). After stirring at 60° C. (bath temperature) 18 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a brown oil. Purification of the crude product by flash chromatography on silica gel eluting with Et2O-hexane (5:95) to give ethyl 2-(1-naphthylamino)propionate (1.726 g, 73%) as a white crystalline solid after trituration with cold hexane. TLC(Et2O-hexane; 2:3) Rf=0.43.
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CS([C@@:15]1(O)[C@:19](S(C)(=O)=O)(O)[C@@H:18]([CH:25](S(C)(=O)=O)[OH:26])[O:17][C@H:16]1[N:31]1[CH:38]=[C:37]([CH3:39])[C:35](=[O:36])[NH:34][C:32]1=[O:33])(=O)=O.Br.CC(O)=O>CN(C=O)C.[Zn]>[C:1]([CH:25]([OH:26])[C@H:18]1[O:17][C@@H:16]([N:31]2[CH:38]=[C:37]([CH3:39])[C:35](=[O:36])[NH:34][C:32]2=[O:33])[CH:15]=[CH:19]1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])c1ccccc1
Reactant: Cc1cn([C@@H]2O[C@H](C(O)S(C)(=O)=O)[C@](O)(S(C)(=O)=O)[C@]2(O)S(C)(=O)=O)c(=O)[nH]c1=O
Agent: Br
Agent: [Na+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cn([C@H]2C=C[C@@H](C(O)C(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Temperature: 90 °C
Reaction time: 5.5 h

Procedure:
To a slurry of powdered sodium benzoate (3.5 g, 24.3 mmol) in DMF (25 ml) at 90° C. was added tris(methanesulfonyl)-5-methyluridine (IX, 5.0 g, 10.2 mmol). The reaction was stirred for 5.5 hours at 90° C. HBr/HOAc (30-32%, 5 ml, 25.1 mmol) was added and the reaction was stirred for one hour. The reaction mixture was cooled to 25° C. and zinc dust (2.0 g, 30.6 mmol) was added. The reaction was stirred for 30 minutes. The excess zinc was removed by filtration and washed with 2×100 ml methanol. To the filtrate was added 100 ml ice-cold water. The resulting slurry was stirred at 0° C. for 30 minutes and then filtered, dried to give 5'-benzoyl-d4T, 2.34 g (71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([O:23]C)=[O:22])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CO.O1CCOCC1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH:13]2[C:21]([OH:23])=[O:22])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2c3ccccc3CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-(4-methoxyphenylsulfonyl)indoline-2-carboxylate (47.1 g, 135.6 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH (15/4/1,1020 ml, 203.4 mmol NaOH, 1.5 eq.), and further 4 M NaOH (153 ml, 610.2 mmol, 4.5 eq.) was added thereto. The solution was stirred overnight at room temperature and then concentrated using a rotary evaporator. Ethyl acetate was added to the residue, and the mixture was washed with 0.5 M KHSO4. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with saturated NaCl solution, dried (sodium sulfate) and concentrated in vacuo. The residue was washed with diethyl ether, filtered and dried.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br>>[F:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([I:1])=[N:3]1
Reactant: Ic1n[nH]c2ncccc12
Reactant: Fc1cccc(CBr)c1F
Product: Fc1cccc(Cn2nc(I)c3cccnc32)c1F
Temperature: 0 °C

Procedure:
Analogously to the synthesis of Example 7A, 54.00 g (215.98 mmol) of 3-iodo-1H-pyrazolo[3,4-b]pyridine (synthesis described in WO 2006/130673 Example 4) were reacted with 50.18 g (237.578) of 2,3-difluorobenzyl bromide. Ice-water was added to the crude product, the mixture was filtered off with suction and the precipitate was washed with isopropanol and pentane and then dried under high vacuum. This gave 73.00 g of the title compound (85% of theory).
Reaction SMILES: [C:1]([C:4]([CH3:45])([CH3:44])[CH2:5][O:6][C:7]([N:9]1[CH2:13][C@@H:12]([N:14]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:42][CH3:43])=[O:8])(O)=[O:2].[Cl-].[NH4+].Cl.C1C=[N:53]C2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:4]([CH3:45])([CH3:44])[CH2:5][O:6][C:7]([N:9]1[CH2:13][C@@H:12]([N:14]([CH2:27][C:28]2[CH:29]=[C:30]([C:38]([F:41])([F:39])[F:40])[CH:31]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:33]=2)[C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:42][CH3:43])=[O:8])(=[O:2])[NH2:53]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OCC(C)(C)C(=O)O
Reactant: On1nnc2cccnc21
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)OCC(C)(C)C(N)=O
Reaction time: 18.5 h
Yield: 39.9 %

Procedure:
To a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 2-carboxy-2-methylpropyl ester (0.016 mmol; 10 mg), ammonium chloride (0.032 mmol; 1.7 mg), WSCD hydrochloride (0.032 mmol; 7.3 mg), HOAt (0.032 mmol; 4.4 mg) in DMF (0.4 ml) is added triethylamine (0.080 mol; 8.1 mg) at room temperature. The reaction mixture is stirred for 18.5 hours at the same temperature, and then quenched with water. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/MeOH) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 2-carbamoyl-2-methyl-propyl ester (4.1 mg, 40%); ESI-MS m/z: 642 [M+1]+, Retention time 2.04 min (condition A).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[C:2]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
Di-tert-butyliminodicarboxylate (4.35 g, 20.0 mmol) was added to a suspension of sodium hydride (0.48 g, 20.0 mmol) in anhydrous DMF (30 mL) at RT. After 30 minutes, a solution of t-butyl 3-bromomethyl-4-nitrobenzoate (6.3 g, 20 mmol) in DMF (15 mL) was added rapidly dropwise. After 16 h, the solvent was evaporated and the residue partitioned between EtOAc (200 mL) and water (40 mL). The organic layer was extracted with water (3×50 mL) and brine (40 mL) and dried finally over Na2SO4. Removal of solvent gave the crude product which was purified on flash chromatography (15:85; EtOAc:Hexane) to give the title compound (81.5%): MS (ES) m/e 453 (M+H)+ ; 1H NMR (400 MHz, CDCl3) δ 7.97-8.10 (m, 3H), 5.16 (s, 2H), 1.62 (s, 9H), 1.49 (s, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ncn1
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
150 mg palladium on charcoal was added to 765 mg 4-(6-methoxy-pyrimidin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 90 mL methanol. The reaction was stirred 3.5 h at RT and 3 bar hydrogen. Then, the reaction was filtered and evaporated to yield 769 mg of the desired product. Rt: 1.31 min (method K), (M+H)+: 294
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:16](CC3OC=CC=3)[N:17]=[C:18]([CH3:19])[C:3]=12.S(=O)(=O)(O)O>>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[NH:16][N:17]=[C:18]([CH3:19])[C:3]=12
Reactant: Cc1nn(Cc2ccco2)c2ncc(C(=O)c3ccccc3)c(N)c12
Agent: O=S(=O)(O)O
Product: Cc1n[nH]c2ncc(C(=O)c3ccccc3)c(N)c12

Procedure:
4-amino-5-benzoyl-3-methyl-1-(2-furanylmethyl)-1H-pyrazolo[3,4-b]pyridine is treated with concentrated sulfuric acid according to the procedure of Example 4 b to obtain 4-amino-5-benzoyl-3-methyl-1H-pyrazolo[3,4-b]pyridine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=2)[C:3]=1[C:22]#[N:23].[CH2:24]([O:26][CH:27](OCC)OCC)[CH3:25]>C(O)C>[C:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:22]#[N:23])=[C:2]([N:1]=[CH:27][O:26][CH2:24][CH3:25])[NH:6][N:5]=2)=[CH:13][CH:12]=1)([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2n[nH]c(N)c2C#N)cc1
Solvent: CCO
Product: CCOC=Nc1[nH]nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)c1C#N
Temperature: 120 °C

Procedure:
With stirring, a mixture of 13.8 g (43.9 mmol) of 5-amino-3-[4-(N-BOC-amino)-phenylamino]-4-cyano-pyrazole and 138 ml of orthoformic acid triethyl ester is heated at 120° C. for 3 hours, care being taken to ensure that the ethanol formed in the course of the reaction is distilled off from the reaction mixture. Cooling to RT, filtering and washing the filter residue with ethanol yield the title compound; m.p. 180-182° C.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]([C:15](=[O:23])[CH:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:19]([S:18][CH2:17][CH:16]([CH3:22])[C:15]([N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][C:6]([OH:24])=[O:5])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude N-(3-acetylthio-2-methylpropanoyl)-N-phenylglycine tert-butyl ester (25 g, 0.0712 mol) was dissolved in a mixture of anisole (40 ml) and trifluoroacetic acid (125 ml). The resulting red solution was stirred overnight at room temperature. The solvent was evaporated and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous sodium bicarbonate layer was acidified cautiously with concentrated hydrochloric acid to pH 4-5. The product was extracted several times into chloroform, washed twice with water, and dried over magnesium sulfate. Filtration and evaporation of the extract afforded the crude product as an orange oil which was further purified by HPLC, eluting with ethyl acetate/n-hexane/acetic acid (40:60:1), to afford pure product (7.5 g., 36%) as a pale yellow oil. The product was crystallized from diethyl ether to afford colorless prisms, m.p. 94°-94.5° C.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2OC)=NC=1CC.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:40]([C:58]([O:60][CH3:61])=[O:59])=[N:41][C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[OH:57])=[C:43]([O:45][CH3:46])[N:44]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:40]([C:58]([O:60][CH3:61])=[O:59])=[N:41][C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[O:57][CH2:2][CH3:3])=[C:43]([O:45][CH3:46])[N:44]=1
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(OC)nc1-c1ccc(Cl)cc1Cl
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C(=O)OC)c(-c2ccc(Cl)cc2Cl)nc1OC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 1.13-0.20, 3.15, 3.55-3.58, 3.66-3.70, 3.76, 4.02, 4.41, 5.75-5.79, 6.16, 7.25-7.34, 7.48, 7.59-7.61; MS (ESI+) for C24H23Cl2N3O4 m/z 488 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:15]([N:17](CC)CC)C.CCOC(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
4-Chlorobenzenesulfonyl chloride (10 g, 47 mmol) was added to a solution of methylamine hydrochloride (3.5 g, 52 mmol) and triethylamine (16.5 ml, 12.0 g, 119 mmol) in dichloromethane (100 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was reduced and chromatography (30% EtOAc/70% hexanes) afforded 4-chloro-N-methylbenzenesulfonamide (7.9 g, 81%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:31]=[CH:32][C:27]([CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCCCc1ccc(N2CCNCC2)cc1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Product: CCCCc1ccc(N2CCN(C(=S)Nc3nc4ccccc4nc3OC)CC2)cc1
Yield: 62.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(4-butylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH:12]([C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:21]=1)[C:13](=O)[CH3:14]>O1CCOCC1>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[S:9][C:8]([NH:7][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[N:10][C:13]=2[CH3:14])=[CH:21][C:20]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: NC(=S)Nc1cnccn1
Reactant: CC(=O)C(Br)c1ccc(Cl)c(S(N)(=O)=O)c1
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(Cl)c(S(N)(=O)=O)c1
Temperature: 70 °C

Procedure:
Pyrazin-2-yl-thiourea (1a) (0.07 g, 0.57 mmol) is added to a stirred solution of 5-(1-Bromo-2-oxo-propyl)-2-chloro-benzenesulfonamide (33b) (0.15 g, 0.46 mmol) in 1,4-dioxan (10 ml) at room temperature. The reaction mixture is heated to 70° C. for 2 h. The resulting precipitate is removed by filtration and dried under vacuum to give the titled compound
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)=[N:8][OH:9].[OH-].[K+].C(OCCO)C>[Cu](Cl)Cl.CCCCCC>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([C:7]2[C:3]3[S:4][CH:5]=[CH:6][C:2]=3[O:9][N:8]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(C(=NO)c2sccc2Br)c1
Agent: Cl[Cu]Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCO
Solvent: CCCCCC
Product: COc1cccc(-c2noc3ccsc23)c1
Yield: 67.6 %

Procedure:
Reflux a mixture of (3-bromothiophen-2-yl)-(3-methoxyphenyl)methanone oxime (10 g, 0.032 mol), KOH (3.6 g, 0.064 mol dissolved in 10 mL water) and 2-ethoxyethanol (100 mL) under nitrogen for one hour at 105–110° C. Add copper chloride (0.16 g, 0.0016 mol) whereupon the reaction mixture becomes dark brown in color. Heat the reaction for an additional one hour. Add water and extract the organics into ether. Wash the ether phase with water, dry (MgSO4), filter and concentrate to yield an oil. Purify the oil by column (alumina) chromatography, and elute with 15% ether in hexane to obtain white crystals. Recrystallize the crystals from ether:hexane to yield the title compound (5 g, 68% Yield), m.p. 51–52° C.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([CH3:20])([O:15][Si](C)(C)C)[CH3:14])[CH:7]=[CH:6][C:5]=12.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:20])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C#CC(=O)c1ccc2nonc2c1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)C#CC(=O)c1ccc2nonc2c1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 1.490 mmol) in DCM (15 mL) was added p-TSA (0.341 g, 1.790 mmol) at RT and the reaction mixture was stirred for 3 h. The reaction mixture was then diluted with water (5 mL) and the layers were separated. The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.3 g, 87%) as an oil.