Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH2:13][C:14]#[C:15][Si](C)(C)C)[C:8]2=[O:12])=[CH:4][C:3]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH2:13][C:14]#[CH:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccc(Cl)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCC1(c2ccc(Cl)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
- Desilylation and hydrolysis of ethyl [6,7-dichloro-1-oxo-2-(p-chlorophenyl)-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate with sodium hydroxide in ethanol according to the procedure of Example 1, STEP (c), affords the title compound, m.p. 200°-201°.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH:10]2[CH:6]([CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])([OH:18])[CH2:4][CH2:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C:2]1([CH3:27])[CH:10]2[CH:6]([CH2:7][NH:8][CH2:9]2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])([OH:18])[CH2:4][CH2:3]1
Reactant: COc1ccccc1C1(O)CCC(C)(C)C2CN(C(=O)OC(C)(C)C)CC21
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1C1(O)CCC(C)(C)C2CNCC21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.49 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-t -butyloxycarbonyl-4-perhydroisoindolol in 21 cm3 of dioxane are added 35 cm3 of 7.4 N hydrochloric acid solution in dioxane. The reaction mixture is stirred for 1 hour at room temperature and then concentrated to dryness under reduced pressure (2.7 kPa). 1.47 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-4-perhydroisoindolol hydrochloride are obtained in the form of a white foam.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>O.C(O)C.[Cu]>[N+:21]([C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=1[S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6.5 g of potassium hydroxide in 80 ml of water is treated under a nitrogen atmosphere at 50° C with 10.3 ml of thiophenol and the mixture is then stirred for 30 minutes. After the addition of 0.5 g of copper powder and 22.5 g of 4-chloro-3-nitro-benzotrifluoride in 100 ml of ethanol, the mixture is heated under reflux for 48 hours. After filtration, the mixture is poured into water and extracted with ether. The ethereal phase is washed successively with aqueous sodium carbonate solution, water, aqueous sodium chloride solution, 2-N aqueous hydrochloric acid and water, dried, filtered and evaporated. There is obtained 3-nitro-4-(phenylthio)-benzotrifluoride as a red oil.
Reaction SMILES: [I:1][Si](C)(C)C.[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29]OC=O)=[O:12])([CH3:9])[CH3:8]>ClCCl>[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29][I:1])=[O:12])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCOC=O)CS[C@H]12
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Product: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCI)CS[C@H]12

Procedure:
2.5 ml of iodotrimethylsilane are added at 0° to the solution of 7-trimethylsilylamino-3-(3-formyloxy-1-propen-1-yl)-3-cephem-4-carboxylic acid trimethylsilyl ester obtained in Example 2a) in dichloromethane, and the solution is stirred for 4½ hours at 0°. The NMR-spectroscopic data are identical to the data given in Example 1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:14]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:13][CH:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:14]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:13][CH:10]1[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: OC1O[C@@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
The hydrolysis of methyl 2,3,4,6-tetra-O-benzyl-L-glucopyranoside may be carried out in glacial acetic acid and dilute sulphuric acid as formulated by Tate and Bishop (supra) to produce 2,3,4,6-tetra-O-benzyl-L-glucopyranose which can be reacted with thionyl chloride to form 2,3,4,6-tetra-O-benzyl-L-glucopyranosyl chloride. Halogenation of 2,3,4,6-tetra-O-benzyl-L-glucopyranose with zinc chloride-thionyl chloride results in a homogeneous 2,3,4,6-tetra-O-benzyl α-L-glucopyranosyl chloride product. In an alternative procedure, methyl 2,3,4,6-tetra-O-benzyl-α-L-glucopyranoside may be refluxed with thionyl chloride (48 hours at 5° C.) to produce 2,3,4,6-tetra-O-benzyl-L-glucopyranosyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[N+:23]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([O-:25])=[O:24]>C(OCC)(=O)C.Cl.CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=1)=[O:6]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(O)c1ccccc1Br
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccccc1Br
Temperature: 45 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
2-Bromobenzoic acid (5.02 g, 25.0 mmol) was sealed in a 250 mL flask with stir bar under nitrogen. Dichloromethane (72 mL) was then added and the solution was cooled on ice. Oxalyl chloride (2.19 ml, 25.0 mmol) and N,N-dimethylformamide (17 μL, 0.22 mmol) were added, and the reaction was removed from the ice bath and the resulting suspension was stirred for 20 h with a vent to an oil bubbler. After this time, the pale yellow solution was cooled on ice, then pyridine (4.04 ml, 50.0 mmol) and 3-nitroaniline (3.00 g, 21.7 mmol) were added. The reaction was then removed from the ice bath, and a water condenser was attached to the flask. The reaction was heated in an oil bath at 45° C., and after 1 h LC-MS analysis showed the reaction to be complete. The reaction was diluted with ethyl acetate (250 mL) and 1 M aqueous HCl (100 mL), then the layers were separated and the organic phase was washed again with aqueous HCl, then twice with half-saturated aqueous NaHCO3, then brine. The organics were dried over Na2SO4, filtered, and concentrated to a yellow solid, which was dried and pulverized several times, yielding the title compound (6.89 g, 99%). LRMS (ESI+) (M+H): 321.01.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH:8][C:9](=[O:12])[CH2:10][Cl:11])[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][C:14]1[S:15][CH:16]=[C:17]([CH2:19][N:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[C:9](=[O:12])[CH2:10][Cl:11])[N:18]=1
Reactant: Cc1ccc(C)n1NC(=O)CCl
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(CN(C(=O)CCl)n2c(C)ccc2C)cs1
Yield: 20.8 %

Procedure:
The product of Example 2 (5.04 g), 2-methyl-4-chloromethyl-1,3-thiazole (4 g) and sodium hydride (1.56 g) in 120 ml dry DMF were treated at 0° C. according to the procedure of Example 3. Work-up yielded 1.67 g of title product (chromatographed on silica gel and by h.p.l.c.).
Reaction SMILES: C([N:3]([C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])[C:4](=[O:8])[C:5]([O-])=[O:6])C.[C:30]([Mg]Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[OH:6][CH:5]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:4]([NH:3][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:8]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCN(C(=O)C(=O)[O-])c1c(C)c(C)c2c(c1C)C(c1ccc(C(C)C)cc1)CO2
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)C(O)C(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of ethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate (500 mg, 1.26 mmol) obtained in Example 15 in THF (10 mL) was added dropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride (2.0 M THF solution, 1.9 mL, 3.78 mmol) and the mixture was stirred for 30 minutes. After the reaction solution was warmed to room temperature and was stirred at the same temperature for 1 hour, the reaction solution was added to ice and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to obtain 194 mg (yield: 38%) of the title compound as a diastereomer mixture. Melting point: 165-166° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Br[CH:12]([CH3:14])[CH3:13]>O1CCOCC1>[CH:12]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])([CH3:14])[CH3:13]
Reactant: Nc1cccc(S)c1
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Sc1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a stirring suspension of 25 grams (0.2 mole) of 3-aminothiophenol in 200 ml. of 5N NaOH was added drop-wise a solution of 24.6 grams of 2-bromopropane (0.20 mole; M.W. 123.00) dissolved in 100 ml. of 1,4-dioxane. The resulting suspension was stirred at room temperature overnight and then was extracted with two 500 ml. portions of ethyl ether. The ether extracts were combined, dried over Na2SO4, and evaporated in vacuo to yield 23.5 grams of m-isopropylthioaniline.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([SH:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>C(Cl)Cl>[S:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[S:16][CH2:13][CH2:14]1
Reactant: SCCS
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)SCCS2
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred solution of ethyl 4-oxocyclohexane carboxylate (5 g, 29.41 mmol) and ethane-1,2-dithiol (4.14 g, 44.11 mmol) in DCM (25 mL) was added BF3.Et2O (4.17 g, 29.41 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 2 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a yellow liquid (5.4 g, 75%); 1H NMR (400 MHz, DMSO-d6) δ 4.05 (q, J=7.4 Hz, 2H), 3.34-3.26 (m, 4H), 2.42-2.34 (m, 1H), 2.10-2.02 (m, 2H), 1.96-1.84 (m, 4H), 1.66-1.54 (m, 2H), 1.17 (t, J=7.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](Cl)=[N:8][C:6]=2[N:7]=1.[CH3:21][NH2:22]>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]([NH:22][CH3:21])=[N:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[CH:4][C:5]=3[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CN
Reactant: COc1ccc(-c2cc3cnc(N)nc3nc2Cl)cc1
Solvent: CO
Product: CNc1nc2nc(N)ncc2cc1-c1ccc(OC)cc1

Procedure:
A mixture of 3.4 g of 2-amino-7-chloro-6-(4-methoxyphenyl)-pyrido[2,3-d]pyrimidine from Example 12, 40 mL of anhydrous methylamine, and 10 mL of methanol were heated in a bomb on a steam bath for 4 hours. After cooling, the suspension was washed out of the bomb with 50 mL of methanol/water (50:50) and the solvents were evaporated in vacuo. The solid residue was slurried with 50 mL of water, filtered, and crystallized from ethanol to afford 2.2 g of the title compound 6-(4-methoxyphenyl)-N7 -methyl-pyrido[2,3-d]-pyrimidine-2,7-diamine, mp 270-275° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CN(P(N(C)C)(N(C)C)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:42][C:43]1[C:51]([Cl:52])=[CH:50][CH:49]=[CH:48][C:44]=1[C:45](Cl)=[O:46]>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:42][C:43]1[C:51]([Cl:52])=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[C:7]1[CH3:12])=[O:46]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCOCC3)c2c1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCN1CCOCC1)c(C)n2C(=O)c1cccc(Cl)c1Cl
Temperature: -22 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To 5-methoxy-2-methyl-3-(2-(morpholin-4-yl)ethyl)- 1H-indole (311 mg; 1.13 mmol) in 10 mL dry THF at -78° C. was added HMPA (590 μL; 3.39 mmol), then dropwise KHMDS (0.5M in Tol; 2.5 mL; 1.25 mmol). The solution was stirred 30 min at -22° C. then cooled to -78° C. after which 2,3-dichlorobenzoyl chloride (361 mg; 1.72 mmol) was added. The final mixture was allowed to reach r.t. slowly then stirred 1 h. The mixture was poored in saturated NaHCO3 (25 mL), extracted with EtOAc (2×50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and flash chromatographed (Silica gel; EtOAc) to yield 503 mg (99%) of the title compound.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]2[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=2)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:26]([CH3:42])=[CH:25][N:24]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:22][C:23]4[CH:28]=[C:27]([C:29]5[CH:30]=[C:31]([CH:39]=[CH:40][CH:41]=5)[C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[C:26]([CH3:42])=[CH:25][N:24]=4)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(N)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (144 mg, 0.593 mmol) was placed in an oven-dried flask under nitrogen. Thionyl chloride (1 mL) and N,N-dimethylformamide (0.1 mL) were added and the solution was allowed to stir for 30 minutes at room temperature. The excess thionyl chloride was removed under vacuum and the resulting solid was suspended in 2 mL of anhydrous dichloromethane. This solution was then slowly added to a solution of tert-butyl 3-(2-amino-5-methylpyridin-4-yl)benzoate (129 mg, 0.454 mmol) in 5 mL of anhydrous dichloromethane containing triethylamine (0.165 mL, 1.19 mmol). The resulting mixture was allowed to stir for 15 hours at room temperature. The crude product was evaporated to dryness and then purified on 12 g of silica gel utilizing a gradient of 0-40% ethyl acetate in hexanes to yield the pure product as a yellow solid (162 mg, 0.319 mmol, 70.3%). ESI-MS m/z calc. 508.2. found; 509.1 (M+1)+ Retention time 2.22 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.18 (s, 1H), 7.98-7.96 (m, 1H), 7.89 (s, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.64-7.62 (m, 2H), 7.57 (d, J=1.6 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.7, 8.3 Hz, 1H), 2.14 (s, 3H), 1.55 (s, 9H), 1.51-1.49 (m, 2H) 1.19-1.15 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][O:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:39][C:36]4[NH:37][N:38]=[C:34]([O:33][CH2:32][C:26]5[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=5)[CH:35]=4)=[O:16])=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CC3)CC2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C5CC5)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 3.8 %

Procedure:
4-(4-Cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as outlined for Example 100, starting from ethyl 4-(4-cyclopropylpiperazin-1-yl)benzoate (0.329 g, 1.2 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride (0.343 g, 1.20 mmol) and 2M trimethylaluminium in toluene (1.500 mL, 3.00 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.022 g, 3.84%) as a white solid. 1H NMR (500.13 MHz, DMSOd6) δ 0.34-0.40 (2H, m), 0.45-0.50 (2H, m), 1.67-1.75 (1H, m), 2.67-2.73 (4H, m), 3.24-3.32 (4H, m), 3.78 (6H, s), 5.08 (2H, s), 5.68 (1H, s), 6.42-6.46 (1H, m), 6.58-6.61 (2H, m), 6.95 (2H, d), 7.83 (2H, d), 10.30 (1H, s), 11.01 (1H, s). MS: m/z 478 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14](=[O:35])[N:15]([CH2:32][CH2:33][CH3:34])[C:16](=[O:31])[N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:18]=1[NH2:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[NH:12][C:13]3[C:14](=[O:35])[N:15]([CH2:32][CH2:33][CH3:34])[C:16](=[O:31])[N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)[C:18]=3[N:19]=2)=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C(O)Cc1ccc(F)cc1
Product: CCCn1c(=O)c2[nH]c(Cc3ccc(F)cc3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 4-fluorophenylacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine. By methods well known in the art, 8-(4-fluorobenzyl)-3-[2-(4-nitrophenyl)ethyl]-1-propylxanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-8-(4-fluorobenzyl)-1-propylxanthine.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([C:7]#[N:8])[C:5]#[N:6].O.[NH2:12][NH2:13]>CCO>[NH2:8][C:7]1[C:4]([C:5]#[N:6])=[C:3]([S:2][CH3:1])[NH:13][N:12]=1
Reactant: NN
Reactant: CSC(SC)=C(C#N)C#N
Solvent: O
Solvent: CCO
Product: CSc1[nH]nc(N)c1C#N
Yield: 71.7 %

Procedure:
To a solution of 2-(bis(methylthio)methylene)malononitrile (5.0 g, 29.37 mmol) in EtOH (20 mL) was added a solution of hydrazine hydrate (64% solution in water) (1.469 g, 45.82 mmol) in EtOH (10 mL) dropwise with stirring. The reaction mixture was stirred at room temperature for 1 hr and then at 70° C. overnight. After the reaction mixture was concentrated, the solid residual was trituated with EtOAc and hexanes. The resulting solid was filtered and dried to give compound I-12 (3.243 g, 71.7% yield, 94.7% purity) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2O.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c(O)ccnc12
Product: COc1cccc2c(Cl)ccnc12
Yield: 72.3 %

Procedure:
Compound 16 (2.65 g, 15.1 mmol) was dissolved in POCl3 (4.2 ml, 45.3 mmol) under nitrogen atmosphere and refluxed for 2 h. It was then cooled and concentrated under vacuum. The solid concentrate was taken in a beaker with 200 ml water neutralized with NaHCO3 powder and extracted with EtOAc. The solution was dried over Na2SO4, filtered, and concentrated. This crude product was then purified through column chromatography using ethyl acetate to get 17 as brown solid (2.113 g, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 4.079 (s, 3H), 7.08-7.1 (d, 1H, J=8 Hz), 7.49-7.56 (m, 2H), 7.76-7.78 (d, 1H, J=8 Hz), 8.76-8.77 (d, 1H, J=4 Hz).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH3:6])=[O:4].[F-:11].[K+]>C(N)(=O)C>[F:11][CH:2]([CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([O:5][CH3:6])=[O:4]
Reactant: [F-]
Reactant: CCCCC(Br)C(=O)OC
Agent: CC(N)=O
Agent: [K+]
Product: CCCCC(F)C(=O)OC
Temperature: 105 °C
Reaction time: 6 h

Procedure:
Methyl 2-bromocaproate (40 g) was added to anhydrous potassium fluoride (23 g) in acetamide (23 g) kept at 105° C. The mixture was vigorously stirred at 105° C. for 6 hours. The crude product obtained after the conventional work-up was distilled. Yield; 20 g (71 %), b.p.; 66° C./20 mmHg
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[Cu][C:17]#[N:18]>CN1CCCC1=O>[C:17]([C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1)#[N:18]
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)Nc1ccccc1S2
Yield: 75.8 %

Procedure:
A mixture of 2-chlorophenothiazine (70.12 g), copper (I) cyanide (32.24 g) and N-methylpyrrolidinone (150 ml) were heated at reflux for 23 hours. The reaction mixture was then quenched with water (900 ml) and sodium cyanide (29.4 g) added. After heating the mixture to 30°-40° C. the black gummy product was extracted with ethyl acetate (3×250 ml). The combined ethyl acetate layers were then washed with water (2×300 ml); some brine being used to break an emulsion which formed durng each wash. Then, after drying the solution and subsequent rotary evaporation, a brown yellow solid product of crude 2-cyanophenothiazine (51 g) was obtained. This material was purified by heating it at reflux as a solution in ethanol with added activated charcoal. After filtering the hot solution thrugh Hyflo it was rotary evaporated to near dryness which resulted in a slurry of purified yellow product which was filtered off and dried (33.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH2:9][OH:10])[CH:8]=1.N1C=CN=C1.[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C1COCC1.CN(C=O)C>[C:20]([Si:23]([O:10][CH2:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc([N+](=O)[O-])c(CO)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(CO[Si](C)(C)C(C)(C)C)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of (5-methoxy-2-nitrophenyl)methanol (12.0 g, 65.6 mmol) in anhydrous THF (200 mL) and DMF (20 mL) was added imidazole (9.80 g, 144 mmol). Then TBSCl (11.8 g, 78.6 mmol) was added portionwise at 0° C. and the mixture was stirred at 30° C. for 2 hours. The mixture was quenched with ice-water (100 mL). An EtOAc workup was followed by removal of solvent in vacuo and purification by column chromatography (PE/EtOAc=10/1) to give the product (16.0 g, yield 84%) as a yellow oil.