Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[Si:12]([O:29][C@@H:30]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[C@@H:32]([CH2:33][CH2:34][C@@H:35]3[C@@H:44]2[CH2:43][CH2:42][C@@:40]2([CH3:41])[C@H:36]3[CH2:37][CH2:38][C@@H:39]2[CH:49]=[O:50])[CH2:31]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][CH:49]([C@H:39]1[CH2:38][CH2:37][C@H:36]2[C@H:35]3[C@H:44]([CH2:43][CH2:42][C@:40]12[CH3:41])[C@:45]1([CH3:48])[C@H:32]([CH2:31][C@H:30]([O:29][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:47][CH2:46]1)[CH2:33][CH2:34]3)[OH:50]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(O)C#C[Si](C)(C)C)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of trimethylsilylacetylene (0.24 mL, 1.715 mmol) in anhydrous THF (5.7 mL) at 0° C. was added a solution of n-BuLi (1.07 mL, 1.715 mmol) 1.6 M in hexanes and the resulting mixture was stirred for 2 h. Subsequently, the mixture was cooled to −78° C. and a solution of 3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-carboxaldehyde (310 mg, 0.57 mmol) in THF (5.7 mL) was added and the mixture was stirred at this temperature for 3 h. Quenching of the reaction by the addition of NH4Cl was followed by extraction with ethyl acetate.
Reaction SMILES: C[O:2][C:3]([C:5]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][N:8]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][N:8]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:12])[CH2:9][CH2:10]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[C:29]#[C:30][CH3:31]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)N3CCCC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)N3CCCC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4-carboxylic acid was prepared following the procedure of Example 64 (step 5). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbonyl)-piperidine-4-carboxylic acid methyl ester (250 mg, 0.52 mmol) in 4 ml of tetrahydrofuran:methanol (1:1) and 1N sodium hydroxide (1.03 ml, 1.03 mmol), 150 mg of (62%) of the acid was isolated. HR-MS: m/z Calculated for C24H25NO7S 472.1425; Found 472.1426.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].N([O-])=O.[Na+].[ClH:16]>O1CCOCC1.O>[Cl:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(O)c1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in concentrated HCl (75 mL) and 1,4-dioxane (14.7 mL). The mixture was heated to 70° C. until most of the solids were in solution. The reaction mixture was cooled to 0° C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained below 10° C. during the addition and the stirring was continued for an additional 15 min. at 0° C. This diazonium intermediate was poured into a solution of Cu(I)Cl (3.8 g; 38.9 mmol) in H2O (18.5 mL) and conc. HCl (18.5 mL) at 0° C. The reaction was stirred for 15 min. at 0° C., warmed to 60° C., and stirred for an additional 15 min. The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3×150 mL). The organic layers were combined, washed with brine (1×), dried (Na2SO4), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure 2-chloro-3-nitrophenol 1c1 (48%; 2.7 g) as an orange solid. MS 171.8 (MH)+: Homogeneity by HPLC (TFA) @ 220 nm: 96%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1C(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(C#N)cc(C(=O)Cl)cc1C(C)C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-5-isopropyl-4-methoxybenzoic acid (658 mg), toluene (7 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.33 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (710 mg) as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]1(=O)[O:13][CH2:12][CH2:11][CH2:10]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[CH2:9][CH2:10][CH2:11][C:12]2=[O:13]
Reactant: Cc1ccc(C)cc1
Reactant: O=C1CCCO1
Product: Cc1ccc(C)c2c1CCCC2=O
Yield: 23.2 %

Procedure:
Using the same reactor as in Example 1, 3.20 g of the 10 wt % HSiW/SiO2 catalyst (0.097 mmol-HSiW) as the catalyst produced in Example 1, 100 ml of p-xylene (799 mmol) and 1 ml of γ-butyrolactone (14.8 mmol) were reacted at 196° C. for 3 hours to obtain 5,8-dimethyltetralone (yield based on γ-butyrolactone: 30.4%). After removing the supernatant by filtration, 100 ml of p-xylene (799 mmol) and 1 ml of γ-butyrolactone (14.8 mmol) as raw materials were charged again and then reacted at 196° C. for 3 hours. As a result, 5,8-dimethyltetralone (yield based on γ-butyrolactone: 23.2%) was obtained. The catalyst could be reused.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C:18](=O)[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32[O:28][CH2:27][CH2:26][O:25]3)[CH2:6]1)(=O)C.[NH2:29][OH:30].[OH-].[Na+].Cl.NO>C(O)C>[CH2:26]1[CH2:27][O:28][C:14]2([CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([C:18](=[N:29][OH:30])[CH2:17][C@:15]23[CH3:16])[C@:20]2([CH3:23])[C@H:7]([CH2:6][C@H:5]([OH:4])[CH2:22][CH2:21]2)[CH2:8][CH2:9]4)[O:25]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@@]2(C)[C@H]3CCC23OCCO3)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2C(=NO)C[C@@]2(C)[C@H]1CCC21OCCO1

Procedure:
3α-Acetoxy-17,17-ethylenedioxy-5α-androstan-11-one (1.0 g) was added to a solution of hydroxylamine prepared by addition of 50% aqueous sodium hydroxide (4 ml) to hydroxylamine hydrochloride (2 g) in ethanol (30 ml). After 17 hours reflux most of the solvent was evaporated in vacuo, the residue was diluted with water and the solid (836 mg) was collected by filtration. A portion was recrystallized from aqueous ethanol to afford the title compound m.p. 158°-159°.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O>O.CO.[Pd]>[CH2:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: CC(C)(C)CC=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Reaction time: 48 h
Yield: 72.9 %

Procedure:
L-aspartic acid (4 g, 0.03 mol) was added to a Parr bottle containing a solution of sodium bicarbonate (5.04 g, 0.06 mol) in water (50 mL) to form a clear solution, with effervescence. A solution of 3,3-dimethylbutyraldehyde (3 g, 0.03 mol) in methanol (50 mL) was then added to the Parr bottle, followed by Pd/C (4% palladium on carbon, 50% wet, 0.4 g). The mixture was hydrogenated at 50 psi/room temperature for 2 days. If the reaction was not complete, fresh Pd/C (0.2 g) would be added and hydrogenation continued for an additional 8 hrs. The mixture was filtered through a Celite® bed, and the bed was washed with methanol (20 mL). The filtrate and washings were combined and concentrated under reduced pressure at 40-50° C. The pH of the remaining aqueous solution was adjusted to 3 with concentrated hydrochloric acid. The precipitated solid was filtered and dried in a vacuum oven at 50° C. for 4 hrs to give 4.75 g (73%) of crude N-neohexyl-L-aspartic acid. The crude product was slurried with aqueous ethanol (47.5, 80% ethanol, 20% water) for 15 minutes and filtered to give 3.3 g (51%) of >98% pure N-neohexyl-L-aspartic acid. M.P. 184-186° C.; [α]D +12.35 (c=1, water); NMR (D2O) δ3.37(t, 3H); 2.25-2.65 (m, 4H); 1.27-1.47 (m, 2H); 0.89(s, 9H); Anal. Calc'd. for C10H19NO4 ; C, 55.28; H, 8.81; N, 6.45; Found: C, 55.35; H, 8.86; N, 6.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:28].[I-].N.CCO>>[NH2:28][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: COc1cccc(C2CC3(N=C(SC)N(C)C3=O)c3cc(Br)ccc3O2)c1
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: COc1cccc(C2CC3(N=C(N)N(C)C3=O)c3cc(Br)ccc3O2)c1
Yield: 17.9 %

Procedure:
A solution of 6-bromo-2-(3-methoxyphenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (13 mg) and NH4I (10 mg) in a solution of NH3/EtOH (2 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC to afford 2′-amino-6-bromo-2-(3-methoxyphenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.17 mg, 22%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([O:12][CH3:13])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([O:12][CH3:13])=[O:11])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: COS(=O)c1cc(C(C)=O)ccc1C
Solvent: O
Solvent: ClC(Cl)Cl
Product: COS(=O)c1cc(C(=O)CBr)ccc1C
Temperature: 40 °C
Yield: 89.4 %

Procedure:
In 200 ml of chloroform was dissolved 21.2 g of methyl 5-acetyl-2-methylbenzenesulfinate and then 16.8 g of bromine was added dropwise to the solution with stirring at 40° C. After the reaction was over, the reaction mixture was added to 500 ml of water and the chloroform layer formed was recovered, washed with a saturated aqueous sodium hydrogencarbonate solution, and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off and the crude crystals formed were recrystallized from ethanol to provide 26 g of methyl 5-bromoacetyl-2-methylbenzenesulfinate having a melting point of 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[N:6][C:5]([C:14]3[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)=[CH:4][N:3]=2)=[CH:13][CH:12]=1)#[N:10]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1cnc(Br)cn1
Product: N#Cc1ccc(-c2cnc(-c3ccc(C#N)cc3)cn2)cc1
Yield: 52 %

Procedure:
The same procedure described for 1,4-Bis-(2′-cyanopyridin-5′-yl)phenylene was used by employing 2,5-dibromopyrazine and 4-cyanophenylboronic acid to furnish 74 in 52% yield; mp >300° C. (DMF). 1H NMR (DMSO-d6): δ 7.99 (d, J=8.4 Hz, 4H), 8.39 (d, J=8.4 Hz, 4H), 9.42 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C:10]2=[N:9][N:8]=1.Cl.CCO>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C:10]2=[N:9][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2cnccn2)C1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: c1cnc(-c2nnc3n2CCNC3)cn1
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of tert-butyl 3-(pyrazin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (9.3 g, 30 mmol) in DCM (100 mL) was added 1.25M HCl in EtOH (30 mL, 37.5 mmol). After 3 h, the reaction mixture was concentrated, and the resulting solid was purified by chromatography (SiO2; 10% MeOH in DCM) to provide the desired product as a white solid (3.7 g, 61%). MS (ESI): mass calcd. for C9H10N6, 202.1; m/z found, 203.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 9.35 (d, J=1.4 Hz, 1H), 8.72 (dd, J=2.5, 1.6 Hz, 1H), 8.66 (d, J=2.6 Hz, 1H), 4.50 (t, J=5.6 Hz, 2H), 4.22 (s, 2H), 3.24 (t, J=5.6 Hz, 2H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][N:29]([CH2:31][CH2:32]Cl)C)=[CH:27][C:22]=2[O:21][CH2:20]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>CN(C=O)C>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:29][CH2:31][CH2:32][N:14]3[CH2:15][CH2:16][CH2:17][CH:13]3[C:8]3[CH:9]=[C:10]([CH3:12])[N:11]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:7]=3)=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: Cc1cc(C2CCCN2)nc(-n2ccnc2)n1
Reactant: CN(CCCl)Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2CCCN2CCNCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Temperature: 80 °C
Yield: 60.7 %

Procedure:
A solution of 2-imidazol-1-yl-4-methyl-6-pyrrolidin-2-yl-pyrimidine (2.1 g, 9.2 mmol) in DMF (15 mL) was added all at once to a stirred mixture of benzo[1,3]dioxol-5-ylmethyl-(2-chloro-ethyl)-methyl-amine hydrochloride salt (2.2 g, 8.1 mmol), DMF (10 mL) and diisopropylethylamine (2.5 mL) at ambient temperature under nitrogen. A catalytic amount of potassium iodide (340 mg, 2.0 mmol) is then added. The mixture is heated to 80° C. for 3 h. The solution is then cooled to room temperature, quenched into 200 mL of 1N dibasic potassium phosphate solution (pH 9), and extracted with ethyl acetate. The combined organics are dried over MgSO4, filtered and concentrated to a red residue. Purification via silica gel column chromatography (DCM to 4:1 DCM/MeOH) gave 2.0 g (52%) of benzo[1,3]dioxol-5-ylmethyl-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine as a red oil. [M+H]+ 421.30; 1H-NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.89 (s, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 6.78 (s, 1H), 6.67 (m, 2 H), 5.88 (s, 2H), 3.52 (t, 1H, J=6.8 Hz), 3.6 (m, 3H), 2.77 (m, 1H), 2.2-2.6 (m, 8H), 1.62-1.95 (m, 3H). 13C-NMR (100 MHz, CDCl3) δ 175.7, 169.6, 154.0, 147.6, 146.5, 136.2, 132.8, 130.1, 121.9, 116.6, 115.0, 109.2, 107.8, 100.8, 69.8, 62.3, 56.0, 54.3, 53.1, 42.5, 33.2, 24.2, 23.4.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([NH:15][CH3:16])=O)=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.O>C1(C)C=CC=CC=1>[F:1][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([NH:15][CH3:16])=[S:35])=[C:5]([NH:17][CH:18]([CH3:20])[CH3:19])[C:4]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A mixture of 3 g (0.009 mol) of product of Example 201 and 7.28 g (0.018 mol) of Lawesson's reagent in 100 ml of toluene was refluxed for 16 days. The reaction mixture was cooled to 25° C., poured into H2O, and extracted with ethyl acetate. The organic phase was dried (MgSO4), and concentrated in vacuo to 1.4 g of a brown oil. Chromatography using 10% ethyl acetate/cyclohexane as an eluting solvent afforded 0.35 g (11%) of product as a beige solid: mp 129°-131° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH3:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:17])=[O:12])=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 2-(4-methoxyphenyl)acetic acid (500 mg, 3.00 mmol) in DCM (30 ml) was added thionyl chloride (0.4 ml, 4.5 mmol) at 0° C. The reaction mixture was allowed to warm up to room temperature and continued to stirred overnight. Then aqueous ammonia (2 ml) was added to the reaction mixture. The white solid forming was filtered and dried under vacuum to obtained 350 mg (70%) of 2-(4-methoxyphenyl)acetamide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:13]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
8.77 g of 4-nitrobenzoic acid (52.5 mM) were dissolved in 400 ml of THF and 53.1 g of triethylamine (525.0 mM). The solution was cooled to −30° C. and 6.01 g of methansulfochloride (52.5 mM) were added dropwise. The mixture was stirred for 1 h at this temperature, then 6.95 g of 4-nitrophenol (50.0 mM) were added at once, followed by 250 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, the reaction mixture was filtered, the cake was washed with THF and the filtrate was evaporated to dryness. The residue was purified by chromatography using silica gel and dichloromethane to give 11.0 g (38.2 mM, 76%) of 4-nitrophenyl 4-nitrobenzoate as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CC(C)=O>[OH:15][CH:14]([C:13]([OH:17])=[O:16])[NH:7][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(C)cc(C(N)=O)c1
Reactant: O=CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)cc(C(=O)NC(O)C(=O)O)c1

Procedure:
A mixture of 3,5-dimethylbenzamide (22.6 g, 0.15 mol) and glyoxylic acid monohydrate (15.3 g, 0.17 mol) in acetone (120 ml) is heated under nitrogen atmosphere at reflux for 6 h. The solvent is evaporated in vacuo to give 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine. To a solution of 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine in methanol (350 ml) is added concentrated sulfuric acid (4.6 ml) at room temperature. The mixture is stirred for 2 days and then concentrated in vacuo. The residue is diluted with ethyl acetate, washed with two portions of saturated sodium bicarbonate solution and with two portions of brine. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give 2-methoxy-N-(3,5-dimethyl benzoyl)glycine methyl ester.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[NH:8].C1C=CC=CC=1.[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>O>[CH3:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[N:8][C:24]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=1)=[O:25]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN1CCCC1=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)N=C2CCCN2C)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 6.73 g. (0.05 mole) of 1 -methyl-2 -iminopyrrolidine hydrochloride in 100 ml. of benzene is added 2 ml. of water followed by 5 ml. of 50 % NaOH. After stirring for 5 min., the benzene layer is decanted onto anhydrous potassium carbonate. The extraction is repeated twice with 75 ml. portions of fresh benzene. The combined extracts are filtered from drying agent (dicalite pad and suction). To the filtrate is added in one portion with stirring 6.66 g. (0.05 mole) of p-tolylisocyanate. After stirring for 5 hours, the solution is taken to dryness in vacuo and the resulting solid is recrystallized from ethyl acetate to give 1 -(1 -methyl-2 -pyrrolidylidene)-3 -p-tolylurea, m.p. = 136°-137° C. A final recrystallization from acetone shows the product melting at 149°-150° C. Thin layer chromatography (TLC) indicates both samples to be identical in purity. Apparently the two melting points represent polymorphic forms.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][CH2:21][CH2:22][N:23]=2)=[CH:14][CH:13]=1.CC(C)([O-])C.[K+].CC(C)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:23]3[CH2:22][CH2:21][NH:20][C:19]=23)=[CH:16][CH:17]=1
Reactant: Clc1ccc(CC2=NCCN2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=c1c2cccnc2c(-c2ccc(Cl)cc2)c2n1CCN2
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Add a solution of 2-chloro-3-pyridinylcarbonyl chloride (4.4 g) in tetrahydrofuran (55 ml) to a stirred, cooled mixture of 2-(4-chlorophenyl)methylimidazoline (4.9 g), potassium tert.-butoxide (2.8 g) and tetrahydrofuran (200 ml). Use a bath of ice and acetone for cooling. Keep the reaction mixture in the bath for 15 minutes, and then allow it to warm to 20° C. over another 15 minutes. To the warmed mixture, add a second portion (2.8 g) of potassium tert.-butoxide; allow the reaction mixture to stir at 20° C. overnight. Evaporate solvent, partition the residue between chloroform and water, and dry the chloroform solution Use sodium sulfate as a drying agent. Filter the dried solution, evaporate the solvent, and crystallize the residue from acetonitrile to obtain 10-(4-chlorophenyl)-2,3-dihydro-imidazo[1,2-g]-[1,6]naphthyridin-5(1H)-one, mp 260°-262° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: O=C(Cl)OCc1ccccc1
Product: CSc1nc(-c2cccc(NC(=O)OCc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with benzyl chloroformate (368 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.