Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[C:19]([C:21]([C:23]2[C:31]3[C:30](Cl)=[N:29][CH:28]=[N:27][C:26]=3[N:25]([CH:33]([CH3:35])[CH3:34])[CH:24]=2)=[O:22])[CH:18]=[C:17]([O:36][CH3:37])[N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH-].[NH4+:39]>O1CCOCC1>[NH2:39][C:30]1[C:31]2[C:23]([C:21]([C:19]3[CH:18]=[C:17]([O:36][CH3:37])[N:16]=[C:15]([NH2:14])[CH:20]=3)=[O:22])=[CH:24][N:25]([CH:33]([CH3:34])[CH3:35])[C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(Cl)c23)cc(N=C(c2ccccc2)c2ccccc2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Temperature: 45 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
[2-(Benzhydrylidene-amino)-6-methoxy-pyridin-4-yl]-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (7.31 g, 14.3 mmol) was added to a solution of ammonium hydroxide (150 mL) in dioxane (150 mL) and stirred at 45° C. in a sealed tube for 12 h. The reaction mixture was concentrated in vacuo, dissolved in hot CH2Cl2 (150 mL), and washed with water (3×100 mL). The aqueous layer was extracted with CH2Cl2 (3×100 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound as a yellow solid (3.43 g, 73%). MS: 327.2 (MH−); HPLC Rf: 2.1 min. (HPLC method 2).
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[CH:37]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])([CH3:39])[CH3:38]>CN(C=O)C>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([CH:37]([CH3:39])[CH3:38])[CH:41]=2)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Reactant: CC(C)c1cccc(N)c1
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cnc5ccccc45)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.10 mmol, 30 mg) and triethylamine (0.20 mmol, 0.028 mL) in 1.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.12 mmol, 0.072 mL). After 15 min at rt, 3-isopropylaniline (0.15 mmol, 0.021 mL) was added and the reaction stirred at rt for 4 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc/hexane to give the title compound as a light beige solid (22 mg, 52%).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:47]([O:48]CC2C=CC=CC=2)[C@H:46]([O:56][C@@H:57]2[O:86][C@H:85]([CH2:87][F:88])[C@@H:76]([O:77]CC3C=CC=CC=3)[C@H:67]([O:68]CC3C=CC=CC=3)[C@H:58]2[O:59]CC2C=CC=CC=2)[C@@H:45]([CH2:89][O:90]CC2C=CC=CC=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[F:88][CH2:87][C@H:85]1[O:86][C@@H:57]([O:56][C@@H:46]2[C@@H:45]([CH2:89][OH:90])[O:44][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[CH2:15][NH:14][C@@H:13]3[CH2:35][OH:36])[C@H:9]([OH:8])[C@H:47]2[OH:48])[C@H:58]([OH:59])[C@@H:67]([OH:68])[C@@H:76]1[OH:77]
Reactant: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O[C@@H]3O[C@H](CF)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: OC[C@H]1NC[C@@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CF)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reaction time: 2 h
Yield: 52.4 %

Procedure:
The compound (126.0 mg, 0.096 mmol) synthesized in Example 4 (4c) was dissolved in methanol (10 mL) containing 1% aqueous hydrochloric acid solution and 20% palladium hydroxide-carbon (100 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 2 hours. After the solvent was removed by celite filtration, 28% ammonia water (0.5 mL) was added thereto, followed by stirring of the mixture for 10 minutes. After the solvent was distilled off under reduced pressure and the aqueous solution (100 mL) was subjected to ion exchange resin (Dowex 50w×8), it was eluted with 1% ammonia water (100 mL). The ammonia water containing the desired compound was concentrated under reduced pressure and the residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (23.1 mg, 52%) as colorless amorphous matter.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.Cl.Cl[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([C:31]5[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=5)[CH2:22][CH2:23]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(c4ccncc4)CC3)ccc2n1CC1CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(cyclopropylmethyl)-2-neopentyl-5-(piperidin-4-ylmethylsulfonyl)-1H-benzo[d]imidazole (STEP D, 25 mg, 0.062 mmol), 4-chloropyridine hydrochloride (19 mg, 0.12 mmol) and triethylamine (35 microL, 0.25 mmol) in ethanol was stirred at 150° C. under microwave for 3 h. The solvent was removed. The residue was diluted with ethyl acetate and saturated sodium bicarbonate aqueous solution to separate. The aqueous layer was extracted with ethyl acetate (3 mL×2) and the organic layer was filtered through magnesium sulfate column. The filtrate was concentrated in vacuo. The residue was purified by prep-LC-MS (“process A”).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH:6]([CH:10]=[O:11])[C:5]([CH3:12])=[CH:4][CH2:3]1.[OH-].[K+].[Cl-].[Na+]>CO>[CH3:1][CH:2]1[C:7]([CH3:8])([CH3:9])[C:6]([CH:10]=[O:11])=[C:5]([CH3:12])[CH2:4][CH2:3]1
Reactant: CC1=CCC(C)C(C)(C)C1C=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C=O)C(C)(C)C(C)CC1
Temperature: 0 °C
Reaction time: 1.33 h

Procedure:
16.6 g of 5-methyl-α-cyclocitral were added dropwise, at 0°-5° C., to a solution of 6.4 g of KOH in 110 ml of methanol, after which the reaction mixture was kept for 80 minutes at 0°-5° C. It was then poured onto 250 ml of ice water and the mixture was saturated with sodium chloride and extracted 5 times with 50 ml of ether at a time. The combined extracts were washed twice with 50 ml of saturated sodium chloride solution at a time, and were dried with anhydrous sodium sulfate.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([NH:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[C:13]([CH3:31])=[C:12]([F:32])[CH:11]=1)[CH3:7]>CN(C=O)C>[CH2:1]([NH:3][C:4]([N:28]1[CH2:29][CH2:30][CH:25]([C:20]2[C:19]3[C:23](=[CH:24][C:16]([C:14]4[CH:15]=[C:10]([C:9]([NH:8][CH2:6][CH3:7])=[O:33])[CH:11]=[C:12]([F:32])[C:13]=4[CH3:31])=[CH:17][CH:18]=3)[NH:22][N:21]=2)[CH2:26][CH2:27]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4CCNCC4)n[nH]c3c2)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4CCN(C(=O)NCC)CC4)n[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl isocyanate (6.5 μL) and N-ethyl-3-fluoro-4-methyl-5-[3-(4-piperidinyl)-1H-indazol-6-yl]benzamide (Intermediate 22, 30 mg) in DMF (3 mL) was stirred at room temperature under nitrogen for 30 min. The solvent was removed under vacuum and the residue was purified by preparative HPLC to give the title compound as a white solid (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[N:11](COCC[Si](C)(C)C)[CH:10]=1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:16]([NH:18][C@H:19]([C:21]3[N:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:25](=[O:33])[C:24]4=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]4[N:22]=3)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=2[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1c[nH]c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 86.5 %

Procedure:
(S)-2-(1-((5-(2-Methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) and a solution of ammonia (7N in methanol, 1 mL, 7.0 mmol) according to the method described in Example 27 to give 34 mg (85% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2ccc(C#N)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(Cc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 26-3 (0.391 g, 1.75 mmol) in methylene chloride (6 ml) cooled in an ice-bath in a 3-necked round bottom flask equipped with a nitrogen inlet and rubber septum was added 1.0M boron tribromide in methylene chloride (3.9 ml, 3.9 mmol) via syringe. The resulting mixture was stirred 18 h while warming to ambient temperature. Water (7 ml) was added and the mixture was extracted with ether (35 ml). The organic fraction was washed with brine (10 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:5 increasing to 1:3), to give product 26-4 as a white solid, mp: 163°-164° C.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:17]C)(=O)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[Na]>CO>[C:12]([O:14][CH2:15][C:5]1[O:6][CH:2]=[CH:3][CH:4]=1)(=[O:13])[CH2:11][CH2:10][CH2:9][C:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: COC(=O)CCCC(=O)OC
Reactant: OCc1ccco1
Agent: [Na]
Solvent: CO
Product: O=C(CCCC(=O)OCc1ccco1)OCc1ccco1
Reaction time: 4 h

Procedure:
196 parts by wt. of furfuryl alcohol and 160 parts by wt. dimethyl glutarate (stoichiometric proportions) were mixed and 0.5-0.75% wt. sodium metal added. The mixture was heated to a temperature in the range from 214°-240° F. under a nitrogen atmoshpere. Methanol was evolved and removed as the reaction progressed. After a period of 4 hours, a waxy solid was obtained. After washing the product with water, the residure was a liquid which was identified as difurfuryl glutarate by gas chromatography and mass spectrometric analysis.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH:23]=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:25][NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][N:26]([CH3:25])[CH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12]
Reactant: CNCCN(C)C
Reactant: O=Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(C)CCN(C)Cc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1

Procedure:
3-(Naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.17 g, 0.5 mmol), trimethyl ethylene diamine (0.6 mmol) and sodium triacetoxyborohydride (0.7 mmol) in dichloroethane (5 mL) was stirred at room temperature for 24 hrs. After completion, the solvent was removed in vacuo, crude material dispersed in water and the pH brought to 3.4. Solid material was filtered off and washed with cold water to afford after drying the target material as a free base. The latter was converted into hydrochloride salt by dissolution in methanol, followed by treatment with the excess of 2N HCl and the evacuation of the volatiles in vacuo to afford the title compound hydrochloride salt, mp>200° C.; MS (APPI) 423 [M+H]
Reaction SMILES: [O:1]=[C:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1.OO.[OH-].[Na+].O.O.O.O.O.S([O-])([O-])(=[O:29])=S.[Na+].[Na+]>CO.O.C(OCC)(=O)C>[O:29]=[C:2]1[CH2:3][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:5][O:1]1
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)COC(=O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
567 ml solution of 37.8 g tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate in methanol was cooled on ice water, and 43 g of 30% aqueous hydrogen peroxide was added dropwise thereinto. 63 ml of 1 N aqueous sodium hydroxide was added dropwise thereto, and the mixture was stirred at room temperature for 2 hr. 1000 ml ethyl acetate, 600 ml water and 100 ml saturated aqueous sodium thiosulfate pentahydrate were added thereto, and the organic layer was recovered. The extracted solution was washed with brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated to give 28.4 g of tert-butyl 3-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH2:36][CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)=[O:22])(=[O:15])=[O:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: NCCCn1ccnc1
Product: O=C(NCCCn1ccnc1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0316 cm3 of N-(3-aminopropyl)imidazole. 54 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide are thus obtained in the form of a yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 1.97 (mt, 2H), 2.98 (s, 3H), 3.25 (mt, 2H), 3.81 (mt, 2H), 4.02 (t, J=7 Hz, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), from 6.85 to 6.95 (mt, 2H), 7.36 (d, J =8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.56 (t, J=5.5 Hz, 1H)].
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl>CO.O>[NH:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([NH:20][C:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:22]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of (R)-tert-butyl 3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (20 g, 42.5 mmol) in MeOH (100 mL) was added conc. HCl (100 mL) at 0° C. and the reaction mixture was stirred for 1.5 h. The solvent was removed in vacuo to give a residue which was dissolved in water (50 mL). The aqueous phase was washed with ether and the aqueous phase was adjusted to a pH 10. The aqueous layer was then extracted with EtOAc (3×30 mL), combined, dried (Na2SO4) and concentrated in vacuo to give the titled compound (15 g, 95%). 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.42 (d, J=3.6 Hz, 1H), 7.28 (d, J=m 8.8 Hz, 2H), 6.77 (d, J=3.6 Hz, 1H), 6.43 (bs, 1H), 4.51 (bs, 1H), 3.18-3.09 (m, 3H), 2.95-2.84 (m, 2H), 2.37 (s, 3H), 1.95-1.88 (m, 2H), 1.81-1.78 (m, 1H), 1.66-1.63 (m, 1H). LCMS [M+1]: 372.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@@H:8]([OH:10])[CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:33]1[C:34]([N+:39]([O-:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(=O)=O.C1(C)C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C@H:8]([O:10][C:33]2[C:34]([N+:39]([O-:41])=[O:40])=[N:35][CH:36]=[CH:37][CH:38]=2)[CH3:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: COc1ccc(F)cc1[C@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1[C@@H](C)Oc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To an ice cooled solution (0° C.) of (S)-1-(5-fluoro-2-methoxy-phenyl)-ethanol (see H. C. Brown, Tet. Letts., 35 (14), 2141-4, 1994. Optical purity of alcohol: >99.5% e.e. (based on SFC on a chiral column: Chiralpak IA (250*4.6 mm i.d.), eluent 5% methanol alcohol in carbon dioxide, Flow rate 4 mL/min, temp. 40° C., back pressure 150 bar, Rt=2.16 min (opposite enantiomer Rt=2.35 min))) (2.00 g, 11.7 mmol), triphenylphosphine (3.54 g, 13.5 mmol, 1.15 eq.) and 3-hydroxy-2-nitro-pyridine (1.81 g, 12.9 mmol, 1.1 eq) in toluene (100 mL) was added a solution of diisopropyl azodicarboxylate (2.73 g, 13.5 mmol, 1.15 eq.) in toluene (20 mL) at such a rate as to maintain the temperature below 10° C. The resulting mixture was stirred at room temperature for 18 hr. The crude reaction mixture was extracted with aqueous potassium hydroxide solution (2M, 2×50 mL). The organic phase was washed with brine and dried over magnesium sulphate before filtering. The filtrate was evaporated under reduced pressure to give an orange semi solid material. This material was suspended in diethyl ether and heptane (80:20 by volume) and filtered. This filtrate was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of diethyl ether in heptane (50:50 to 80:20 by volume) to produce the title compound as a pale yellow oil (3.48 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:20]Br>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=2[CH2:19][Br:20])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrBr
Reactant: Cc1c(-c2cccc([N+](=O)[O-])c2)cccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=[N+]([O-])c1cccc(-c2cccc([N+](=O)[O-])c2CBr)c1
Yield: 77.4 %

Procedure:
The procedure of Example 8 was used except that the starting material was 0.80 g of 2-(3-nitrophenyl)-6-nitrotoluene which was reacted with 0.49 g of bromine and 33 mg of benzoyl peroxide. In this way, 0.80 g (77% yield) of yellowish crystals were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cccc(OC)c1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(OC)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-methoxyphenyl)acetate hydrochloride (prepared by the Bucherer Modification of the Strecker procedure as described in J. P. Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp=163-170° C.). The reaction was monitored by tlc (Rf=0.45 in 9:1 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([C:33]([F:32])([F:43])[F:44])[CH:35]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccc(C(F)(F)F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (80 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3-trifluoromethylbenzoyl chloride (0.42 mL, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the solid was rinsed with CH2Cl2 (15 mL) and acetone (15 mL). The solid was then recrystallized with MeOH to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-trifluoromethyl-benzamide as a white solid (0.5 g, 54%): mp, 241-243° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.4 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.53-2.65 (m, 2H), 2.85-2.93 (m, 1H), 4.96 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.46-7.84 (m, 6H), 9.33 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.49, 48.86, 106.93, 110.58, 110.69, 110.82, 110.93, 121.99, 127.21, 131.54, 133.20, 134.83, 137.42, 138.62, 160.51, 160.67, 163.78, 163.95, 164.10, 166.92, 167.48, 169.81, 172.73. Anal Calcd for C21H15FN3O5: C, 59.02; H, 3.54; N, 9.83; F, 8.89. Found: C, 58.90; H, 3.15; N, 9.73; F, 9.08.