Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[C:12]1([CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][C:26]#[N:27])(=[O:24])=[O:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:25](/[S:22]([NH:21][CH2:20][CH2:19][CH2:18][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:24])=[O:23])\[C:26]#[N:27])[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: N#CCS(=O)(=O)NCCCc1ccccc1
Product: Cc1cc(/C=C(\C#N)S(=O)(=O)NCCCc2ccccc2)cc(C)c1O

Procedure:
M45 was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and N-3-phenyl-n-propyl cyanomethylsulfonamide under similar conditions as described for M40 (part B).
Reaction SMILES: [CH2:1]([N:4]([CH2:34][CH2:35][CH3:36])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]3[C:27](=O)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=O)[CH:15]=2)[CH:10]1OCOC)[CH2:2][CH3:3]>O1CCOCC1>[CH2:34]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][N:19]3[CH:27]=[C:26]4[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]4)=[CH:20]3)[CH:15]=2)[CH:10]=1)[CH2:35][CH3:36]
Reactant: CCCN(CCC)CCCCC1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1OCOC
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCC1=Cc2ccc(Cn3cc4ccccc4c3)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.5 %

Procedure:
The compound (113.0 mg) obtained in Example 11-11 was dissolved in dioxane (2.2 ml) and the whole was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated saline solution. The resultant was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (98.8 mg) as a yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][OH:23])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([N+:15]([O-:17])=[O:16])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:34])=[O:33]
Reactant: COC(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
A stirred solution of methyl 5-[bis(2-hydroxyethyl)amino]-2,4-dinitrobenzoate [Palmer et al., J. Med. Chem 1994, 37, 2175] (5.50 g, 16.7 mmol) and Et3N (5.82 mL, 41.8 mmol) in dry CH2Cl2 (50 mL) was treated dropwise at 0° C. with MsCl (3.14 mL, 40.0 mmol). After 30 min, 10% aqueous KHCO3 (100 mL) was added, and the mixture was stirred for a further 30 min at 0° C. and then diluted with pet. ether (500 mL). The precipitated product was collected and washed with water and iPr2O to give methyl 5-(bis{2-[(methylsulfonyl)oxy]ethyl}amino)-2,4-dinitrobenzoate (7) (7.44 g, 92%):
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]=2[C:22]2[CH:31]=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[C:29]3[CH:28]=[C:27]([N+:45]([O-])=O)[C:26](=[O:48])[NH:25][C:24]=3[N:23]=2)[CH2:3][CH2:2]1.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:45][C:27]1[C:26](=[O:48])[NH:25][C:24]2[N:23]=[C:22]([C:7]3[C:8]([O:12][CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:31]=[C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[C:29]=2[CH:28]=1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc([N+](=O)[O-])c(=O)[nH]c3n2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc(N)c(=O)[nH]c3n2)cc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a stirred mixture of tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxy-benzyl)oxy]phenyl}-6-nitro-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1- piperidine-carboxylate (0.085 g, 0.129 mmol), iron powder (0.300 g), ethanol (4.5 mL) and water (0.5 mL) was added ammonium chloride (0.100 g). The mixture was stirred at 85° C. for 30 min. After cooled to room temperature, the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl 3-(6-amino-2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]-phenyl}-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate (0.068 g, yield; 84%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([O:17]CC2C=CC=CC=2)=[CH:15][CH:14]=[C:13]([O:25]CC2C=CC=CC=2)[C:12]=1[O:33][CH3:34])[CH3:2].Cl.[H][H]>CCOCC.C(O)C.[Pd]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[CH2:8][NH:9][C:10](=[O:35])[C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([OH:25])[C:12]=1[O:33][CH3:34])[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCC[C@H]1CNC(=O)c1c(OCc2ccccc2)ccc(OCc2ccccc2)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCN1CCC[C@H]1CNC(=O)c1c(O)ccc(O)c1OC
Yield: 113.2 %

Procedure:
A mixture of (S)-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-3,6-dibenzyloxy-2-methoxybenzamide (130 mg, 0.27 mmol), 5% Pd/C (50 mg), 0.5 ml 4 M HCl in ether and 5 ml ethanol was shaken in a hydrogen atmosphere for 1 h. Filtration and evaporation of the solvent gave 90 mg pure title compound as an oily hydrochloride.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:9]([CH2:17][C:18]#[N:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[C:18]([NH2:19])=[CH:17][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:2]1
Reactant: NNc1ccccn1
Reactant: N#CCC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cc(-c2ccccc2)nn1-c1ccccn1
Yield: 80.5 %

Procedure:
To a solution of 1.09 g 2-hydrazinopyridine in 10 ml 5N hydrochloric acid was added 1.45 g benzoylacetonitrile (from Example 2) under stirring. The mixture was refluxed for 3 hrs. After cooling, the solution was neutralized with Na2CO3. The yellow precipitate was filtrated, washed with H2O, and dried to get 1.9 g 1-pyridyl-3-phenyl-5-aminopyrazole.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10]([CH2:11][C@@H:12]([OH:22])[CH2:13][CH2:14]2)=[CH:9][CH2:8]3)[CH2:5][CH2:4]1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C.O>CC(C)=O>[CH2:1]=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[C:9](=[O:25])[CH2:8]3)[CH2:5][CH2:4]1
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: C=C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h

Procedure:
A solution of pregna-5,20-dien-3β-ol (300.5 mg, 1.000 mmol) in 35 ml of acetone was cooled in an ice water bath and 2.67 M Jones reagent (0.71 ml, 1.9 mmol) was added. After stirring 11/2 h a further 0.71 ml of Jones reagent were added and the reaction was continued 45 min, 2-Propanol (1.0 ml) was added and the mixture was poured into 100 ml of water. The mixture was then extracted twice with 50 ml of ethyl acetate and the combined organic extracts were washed with 50 ml of saturated sodium bicarbonate+50 ml of water +50 ml of brine and filtered through a 21 mm dia×22 mm high column of silica gel 60. The column was eluted further with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization of the residue from 95% ethanol gave a light yellow powder (104.6 mg, 0.3348 mmol 33%), m.p. 114-120° C.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9]([CH3:13])=[CH:10][CH2:11]O>C(O)=O>[CH3:6][C:5]([CH2:7][CH2:11][CH:10]=[C:9]([CH3:13])[CH3:8])=[CH:4][C:2](=[O:1])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)=CCO
Solvent: O=CO
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 78 %

Procedure:
800 parts of mesityl oxide, 200 parts of 3-methyl-2-buten-1-ol (prenol) and 2 parts of formic acid are heated at 250°C for 3 hours in a vibrated autoclave holding 2500 parts by volume at a pressure of 60 atmospheres. The reaction mixture is worked up by distillation and gives 190 parts of 4,8-dimethyl-3,7-nonadien-2-one having a boiling point of 60° to 62°C at 0.2 mm. The yield is 78% of theory at a conversion of 63% based on prenol.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2)[CH3:8].[OH-].[Na+].CN([CH:27]=[O:28])C>O>[CH3:8][N:7]([CH2:9][CH:10]1[CH2:12][CH:11]1[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:27]=[O:28])[CH3:6]
Reactant: CN(C)CC1CC1c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)CC1CC1c1ccc2[nH]cc(C=O)c2c1
Reaction time: 0.25 h

Procedure:
Phosphorous oxychloride (0.08 mL, 0.85 mmol, 0.91 equiv.) and dimethyl formamide (0.32 mL, 4.09 mmol, 4.4 equiv.) were combined at room temperature with stirring. After 15 min, N,N-dimethyl-2-(indol-5-yl)cycloprop-1-yl-methylamine was added dropwise in DMF (5 mL). After 2 hs of stirring at room temperature, ice and 1 N NaOH were added, then the mixture was diluted further with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N,N-dimethyl-2-(3-formyl-indol-5-yl)cycloprop-1-yl-methylamine (120 mg) as an oil. 1H NMR (MeOH-d4): δ9.84 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.05 (dd, J=15.5, 1.7 Hz, 1H), 2.59 (dd, J=12.7, 6.7, 1H), 2.35 (s, 6H), 2.30 (m, 1H), 1.80 (m, 1H), 1.20 (m, 1H), 1.05 (m, 1H), and 0.88 (m, 1H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1ON=C(CCC[Br:43])C=1>>[Br:43][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1
Reactant: Cc1cc(CCCCCO)no1
Reactant: Cc1cc(CCCBr)no1
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(CCCCCBr)no1
Yield: 77 %

Procedure:
3-(5-Bromopentyl)-5-methylisoxazole [XXVII; R9 =CH3, Hal=Br] was prepared by reacting 3-(5-hydroxypentyl)-5-methylisoxazole with bromine and triphenylphosphine according to the procedure of part (f) above, and was obtained in 77% yield as an oil, b.p. 140°-150° C. (0.05 mm).
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH3:7][N:8]([CH3:18])[C:9]1[CH:14]=[C:13]([C:15](=O)[CH3:16])[CH:12]=[CH:11][N:10]=1>CO>[CH3:7][N:8]([CH3:18])[C:9]1[CH:14]=[C:13]([C:15](=[N:2][OH:3])[CH3:16])[CH:12]=[CH:11][N:10]=1
Reactant: NO
Reactant: CC(=O)c1ccnc(N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NO)c1ccnc(N(C)C)c1
Reaction time: 0.08 h

Procedure:
To 3.1 g. (45 mmoles) of hydroxylamine hyrochloride in 25 ml. of water and 22.5 ml. of 2 N sodium hydroxide solution was added 4.31 g. (26 mmoles) of 1-(2-dimethylamino-4-pyridyl)-1-ethanone, and the mixture was heated to boiling. After 5 minutes, methanol was added until the mixture became homogeneous. Heating was continued until a precipitate started to appear, and the mixture was then cooled. The solids were filtered, washed with water and dried. Recrystallization from toluene gave 4.03 g. (86%) of product, m.p. 145°-148° C.
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.C([Mg]Cl)(C)C.C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N>C1COCC1>[CH2:27]([O:26][C:24]([C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1)=[O:25])[CH3:28]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Reactant: CCOC(=O)C#N
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a solution of 2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at −40° C. was added dropwise a solution of 2M i-PrMgCl in THF (1 mL). The reaction was allowed to stir for 10 min at −40° C. and then cooled to −78° C., and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. The reaction allowed to attain RT and stirred for 1 h. The reaction was quenched with satd aq NH4Cl, diluted with EtOAc (20 mL) and washed with brine (2×20 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.40 g (74%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C13H21N3O3Si, 296.1 (M+H), found 296.1.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: ClCC1OCCO1
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCC1OCCO1

Procedure:
2,6-Dimethylaniline (75 grams), 2-chloromethyl- 1,3-dioxolane (25 grams), potassium carbonate (35 grams) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux for a period of about 18 hours. After this time the mixture was filtered and distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl-2,6-dimethylaniline.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH2:31]2)=[C:27]([NH2:29])[CH:28]=1>>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6][NH:29][C:27]1[CH:28]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=1[CH:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=2)[CH2:31]1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Yield: 70.1 %

Procedure:
Synthesized from 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (1.2 g) and 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (600 mg) according to an analogous synthetic method to Example 152, the title compound (770 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(CO)cc1
Product: OCc1ccc(Nc2nc(Cl)ncc2F)cc1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-aminobenzylalcohol were reacted to yield 2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.08 (d, 1H, J=2.7 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.40 (d, 2H, J=8.1 Hz), 6.99 (bs, 1H), 4.70 (s, 2H); 19F NMR (CDCl3): −44570 (s, 1F); LCMS: ret. time: 19.57 min.; purity: 99%; MS (m/e): 254 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][NH:25][CH3:26]>CCO>[CH3:24][N:25]([CH3:26])[C:2]1[N:7]2[N:8]=[C:9]([S:21][CH3:22])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: CNC
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: CSc1nn2c(N(C)C)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1

Procedure:
In an analogous manner to that described in Example 5, from 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl) -pyrazolo[1,5-a]pyrimidine and dimethylamine in EtOH there was obtained dimethyl-[5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine as colorless crystals, m.p. >230°.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:16]Br>C(#N)C>[C:1]1([S:7]([CH2:9][Br:16])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccccc1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(CBr)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Methyl phenyl sulfoxide (21.644 g, 154.4 mmol) was dissolved in anhydrous pyridine (27.4 mL, 2.2 eq) and dry acetonitrile (100 mL). The solution was cooled to −40° C. under an argon atmosphere. A solution of bromine (49.4 g, 2 eq) in dry acetonitrile (50 mL) was added slowly, maintaining the same temperature. The mixture was stirred at −40° C. for 1 h and then overnight at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in dichloromethane. The organic layer was washed with Na2S2O3 20%, dried over anhydrous Na2SO4 and concentrated to dryness.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21].[CH3:22]OC(OC)OC.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:22])=[O:14])([CH3:10])[O:9][C:4]=2[C:3]=1[CH2:19][CH2:20][CH3:21]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)O)CC2=O
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OC)CC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the title compound of Example 3 (4.3 g, 14.7 mmole), 6 ml of trimethylorthoformate, and 1.4 ml of sulfuric acid was stirred at room temperature for two hours. The reaction mixture was poured onto stirred ice/water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated to an oil. The oil was purified by chromatography on silica gel, giving 3.7 g of the title compound as a crystalline solid, m.p. 101.5°-102.5°. Structure assignment was consistent with nmr and infrared spectra. ##STR7##
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:22].[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH2:15]([N:4]1[C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:37](=[O:38])[C@H:35]([CH3:36])[NH:34][C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[C:28]([F:30])[CH:29]=[C:24]([F:23])[CH:25]=2)[C:3]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of (3S,7S)-3-amino-1-benzyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (5d) (40 mg) in DCM (2 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (33 mg), HOBt-hydrate (46 mg), EDAC.HCl (39 mg) and N-methyl morpholine (22 mg). The reaction mixture was stirred 1 h at 0° C. and 3 h at RT, then diluted with 30% hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1%-2% MeOH/DCM) to afford a white solid (50 mg, 71%). Sample contains approx. 20% 5A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(N(CC)CC)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CCC2=O)c1ccccc1

Procedure:
5-Aminoindan-1-one (2.5 g) was reacted with benzoyl chloride (2.63 g) in dichloromethane and triethylamine to give 5-benzamidoindan-1-one which was reacted with benzaldehyde in a similar manner to Example 7a) to give N-(2-benzylidene-1-oxoindan-5-yl)benzamide which was reacted with hydrogen peroxide in a similar manner to Example 7b) to give an intermediate which was reacted with hydrazine hydrate in a similar manner to Example 7c) to give -(3N-phenyl-1,4-dihydroindeno[1,2-c]pyrazol-6-yl)benzamide, m.p. 271° C., after chromatography of the reaction mixture.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[C:9]([C:17]([OH:19])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.[CH3:22][O:23]C1C=CC(OC)=CC=1C1C(C(OC)=O)=CC([N+]([O-])=O)=CC=1>>[CH3:21][O:20][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([OH:19])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[C:12]([O:23][CH3:22])[CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(OC)ccc1OC
Reactant: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1ccccc1-c1cc(OC)c([N+](=O)[O-])cc1C(=O)O
Yield: 99 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl 2',5'-dimethoxy-4-nitro-2-biphenylcarboxylate (2.07 g) to afford 1.93 g (99%) of 2',5-dimethoxy-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 2', 5'-dimethoxy-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.64 (d, J=2.5, 1H), 8.43 (dd, J=8.4, 2.6, 1H), 7.67 (d, J=8.5, 1H), 6.94 (m, 2H), 3.80 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][P:2]1(Cl)[N:7]=[P:6](Cl)([Cl:8])[N:5]=[P:4]([Cl:11])(Cl)[N:3]=1.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>>[Cl:1][P:2]1([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=[P:6]([Cl:8])([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[P:4]([Cl:11])([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Product: ClP1(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=N1

Procedure:
Examples 8 to 12 below illustrate embodiments of the invention in which hexachlorocyclotriphosphazene (compound 1) is reacted first with sodium phenoxide to produce an intermediate (trischlorotrisphenoxycyclotriphosphazene), 19 which is then reacted without separation with sodium 4-nitrophenoxide to afford tris(4-nitrophenoxy)tris(phenoxy)cyclotriphosphazene 20. The nitro groups of 20 are reduced to afford the corresponding tris amino compound 21 which is then used according to Scheme I or Scheme II shown in FIG. 2 and FIG. 3, respectively.