Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:13]([F:25])[CH:12]=3)[C:6]=2[N:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[O:34])=[CH:29][CH:28]=1.CC([O-])(C)C.[K+]>C1COCC1>[F:25][C:13]1[CH:12]=[C:11]([N:8]2[C:6]3[N:7]=[C:2]([NH:26][C:27]4[CH:28]=[CH:29][C:30]([C:33]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)=[O:34])=[CH:31][CH:32]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[CH:9]2)[CH:16]=[C:15]([F:17])[C:14]=1[CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Fc1cc(-n2ccc3cnc(Cl)nc32)cc(F)c1CN1CCOCC1
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(Nc3ncc4ccn(-c5cc(F)c(CN6CCOCC6)c(F)c5)c4n3)cc2)CC1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
In a sealed tube, 2-chloro-7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (50.0 mg, 0.130 mmol), (4-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone (42.1 mg, 0.182 mmol), KOtBu (21.1 mg, 0.182 mmol) and SK-CC02-A (12.5 mg, 0.020 mmol, Pd catalyst 2-(Dimethylaminomethyl)-ferrocen-1-yl-palladium(II)-chlorid Dinorbornylphosphin Complex, Fluka No. 44696) are suspended in THF (2 ml) under Ar. The reaction mixture is stirred at 80° C. for 1.5 h, cooled to rt, and then filtered through a Celite plug. The filtrate is concentrated under reduce pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound (2) as a white solid. HPLC: tR=0.89 min (Method A); MS-ES: (M+H)+=548.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1[CH:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=1)=[O:26].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:12]=[C:11]([F:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1[CH:28]=[N:29][C:30]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:31][CH:32]=1)=[O:26]
Reactant: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1
Reactant: CN1CCNCC1
Solvent: O
Product: CN1CCN(c2ccc(C(=O)Nc3cc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)ccc3Cl)cn2)CC1
Temperature: 110 °C

Procedure:
A mixture of 4-chloro-3-(6-chloropyrid-3-ylcarbonylamino)-N-(3-fluoro-5-morpholinophenyl)benzamide (0.2 g) and N-methylpiperazine (1.5 g) was stirred and heated to 110° C. for 20 hours. The mixture was cooled to ambient temperature. Water was added and the mixture was stirred at ambient temperature for 30 minutes. The resultant precipitate was isolated, washed with water and dried. There was thus obtained the title compound (0.18 g); Mass Spectrum: M+H+ 553.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:22])[NH:14][CH2:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([O:23][CH3:24])[N:10]=[C:9](S(C)=O)[N:8]=1.[NH:33]1[CH2:39][CH2:38][CH2:37][C@H:34]1[CH2:35][OH:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:22])[NH:14][CH2:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:11]([O:23][CH3:24])[N:10]=[C:9]([N:33]2[CH2:39][CH2:38][CH2:37][CH:34]2[CH2:35][OH:36])[N:8]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(CNc2nc(S(C)=O)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl
Product: COc1ccc(CNc2nc(N3CCCC3CO)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl

Procedure:
4-(3-Chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylsulfinylpyrimidine (prepared in the above (4)) and L-prolinol is treated in the same manner as Example 321(5) to give 4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-(2-hydroxymethyl-1-pyrrolodinyl)pyrimidine as a colorless crystalline powder 88 mg. mp 153-154° C.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[C:1]([C:5]1[N:6]=[C:7]([Cl:24])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1[nH]c(=O)c2ccccc2c1-c1ccccc1
Product: CC(C)(C)c1nc(Cl)c2ccccc2c1-c1ccccc1

Procedure:
A mixture of 11 g. (0.04 mole) of 3-tert. butyl-4-phenyl isocarbostyril and 40 ml. of phosphorous oxychloride is refluxed for one hour. The excess solvent is removed in vacuo and ice is added to the residue and stirred. The resulting solid is filtered and washed with water and recrystallized from ethanol to give 3-tert.butyl-1-chloro-4-phenyl isoquinoline; m.p. 139°-140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][O:25][C:24](=[O:27])[NH:23]2)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[Cl:14][C:4]1[N:3]=[C:2]([N:23]2[CH:22]([C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:26][O:25][C:24]2=[O:27])[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=1
Reactant: O=C1NC(c2ccc(F)cc2)CO1
Reactant: Cn1cc(-c2cc(Cl)nc(Cl)c2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Cl)nc(N3C(=O)OCC3c3ccc(F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
379 mg of 2,6-dichloro-4-(1-methyl-1H-pyrazol-4-yl)pyridine, 300 mg of 4-(4-fluorophenyl)oxazolidin-2-one, 192 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 705 mg of tripotassium phosphate and 172 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 10 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 212 mg of the objective compound as yellow powder.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13](OC3C=CC=CC=3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC([Cl:29])=C(Cl)C=1>ClC1C=C(C)C=CC=1Cl.ClC1C=CC(Cl)=CC=1Cl.ClC1C(Cl)=C(Cl)C=CC=1>[C:1]1([S:7]([C:10]2[CH:22]=[CH:21][C:13]([Cl:29])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Oc2ccccc2)cc1
Reactant: Clc1ccccc1Cl
Agent: Cc1ccc(Cl)c(Cl)c1
Agent: Clc1cccc(Cl)c1Cl
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=S(=O)(c1ccccc1)c1ccc(Cl)cc1

Procedure:
FIGS. 1 and 2 illustrate the behavior of the new phase transfer catalysts in the formation of 1,1′-(1-methylethylidene)bis[4-[4-(phenylsulfonyl)phenoxy]benzene (CAS No. 90139-53-0). When the P2-EthylMethyl mesylate was used as a PTC at 1.0 mole % in the model reaction in refluxing o-DCB at 180° C. (See 4 (FIG. 1)), the reaction exhibited pseudo-first order kinetics. This indicates that no catalyst decomposition nor diminution in rate was occurring during the reaction. In order to further test the stability of the phosphazenium salt, similar reactions were carried out at higher temperatures, in 3,4-dichlorotoluene (bp=200° C.) (See 6 (FIG. 1)) and in 1,2,4-trichlorobenzene (bp=214° C.) (See 2 (FIG. 1)). As shown in FIG. 1, even at 200° C., essentially linear reaction kinetics were observed, indicating no decomposition of the P2-EthylMethyl mesylate phase transfer catalyst. In trichlorobenzene, only a small amount of decomposition was observed, after 60 minutes (See 2 (FIG. 1)). In this instance only 0.5 mole % catalyst was used, since after initial range-finding experiments it was determined that reaction using 1.0 mole % would be too fast to follow accurately at 214° C.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17]C(O)=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([OH:33])[CH:27]=1.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:23][O:24][C:25]([C:26]1[CH:31]=[CH:30][C:29]2[N:32]=[C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:10][CH:5]6[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]6)[CH2:2]4)[CH2:8]5)=[CH:22][CH:21]=3)[O:33][C:28]=2[CH:27]=1)=[O:34]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Temperature: 140 °C
Yield: 63 %

Procedure:
A mixture of (4-adamantan-1-yl-phenoxymethyl)acetic acid (200.0 mg, 0.70 mmol) and 4-amino-3-hydroxy-benzoic acid methyl ester (164.3 mg, 0.98 mmol) in PPSE (3 mL) was heated at 140° C. for 2 h. At the end of the reaction period, the mixture was taken to dichloromethane and neutralized with 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to afford 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid methyl ester as a white solid (184.0 mg, 63.0% yield).
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:24].[K+]>O>[I:24][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(I)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 4-amino-2-(trifluoromethyl)benzoic acid (10 g, 48.7 mmol, Apollo) in water (43 ml) in an ice-water bath (internal temperature at 5° C.) was added concentrated sulphuric acid specific gravity 1.84 (7 mL, 131 mmol). To the slight suspension was added a solution of sodium nitrite, super free flowing (3.76 g, 54.5 mmol, Aldrich) in ice cold water (20 ml) dropwise. The suspension was stirred in an ice-water bath for 20 min. To the mixture was added a solution of potassium iodide, extra pure briquettes (12.14 g, 73.1 mmol, Acros) in ice cold 1 M sulphuric acid (30 ml). The mixture was allowed to warm to ambient temperature and then heated to 80° C. for 45 min under nitrogen. The mixture was allowed to cool to ambient temperature. The mixture was partitioned between ethyl acetate (300 ml) and water (300 ml). The phases were separated and the organic phase washed with brine (50 ml×2), dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a dark brown solid (16.7 g); LCMS: (System 4) (M-H)−=315, tRET=2.64 min.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2].N([O-])=[O:14].[Na+].NC(N)=O>S(=O)(=O)(O)O>[C:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:14])=[CH:7][C:6]=1[Cl:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(N)cc1Cl
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)c1ccc(O)cc1Cl
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
4-tert-Butyl-3-chloroaniline (690 mg, 3.8 mmol) was dissolved in 12 M sulfuric acid (30 ml) and then heated at 90° C. To the clear solution was added 5 ml of aqueous solution of sodium nitrite (776 mg, 11.3 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 15 minutes. Urea was added to the mixture until excess sodium nitrite was destroyed (by checking starch-iodine test paper). A small amount of cupric sulfate was added to the mixture and then the mixture was stirred at 90° C. for 30 minutes. The resulting organic layer was extracted with ethyl acetate washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=¼ to furnish 0.44 g (64% yield) of the title compound as a brown oil.
Reaction SMILES: ClC1N=C(N2C3C=CC(C#N)=CC=3N=C2)C=NC=1.Cl[C:20]1[N:25]=[C:24]([N:26]2[C:30]3[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=3[N:28]=[CH:27]2)[CH:23]=[N:22][CH:21]=1.[C@@H:37]1([NH2:47])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1>>[C@@H:37]1([NH:47][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[N:22][CH:21]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: N#Cc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Agent: N#Cc1ccc2c(c1)ncn2-c1cncc(Cl)n1
Product: N#Cc1ccc2ncn(-c3cncc(N[C@H]4CCCc5ccccc54)n3)c2c1

Procedure:
In an analogous fashion to Example 1, an approximately 1:1 mixture of 1-(6-chloropyrazin-2-yl)-1H-benzimidazole-5-carbonitrile and 1-(6-chloropyrazin-2-yl)-1H-benzimidazole-6-carbonitrile (100 mg, 0.39 mmol) was condensed with (1S)-1,2,3,4-tetrahydronaphthalen-1-amine (69 mg, 0.47 mmol). The product was obtained as a mixture of regioisomers which were separated by column chromatography using dichloromethane-methanol (95:5) as eluant. From the less polar fractions 1-{6[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylamino]pyrazin-2-yl}-1H-benzimidazole-6-carbonitrile was obtained as a yellow semi-solid (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:24]Cl.CS(F)(=O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CCOC(=O)c1ccc(NCCCc2ccc(Cl)cc2)cc1
Agent: CS(=O)(=O)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1ccc(N(C)CCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 1.0 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate, 20 ml. of dry dichloromethane and 2.5 ml. of methane sulfonyl fluoride is stirred for 18 hours, then refluxed for 3 hours. The solution is poured into 30 ml. of water and adjusted to pH 10 with 10N sodium hydroxide. The dichloromethane layer is separated and saved. The aqueous layer is extracted with two 20 ml. portions of dichloromethane. The organic layers are combined, washed with 10 ml. of water, dried over anhydrous magnesium sulfate, and evaporated to yield 1.80 g. of the desired product as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:22]1([CH2:28][CH2:29][C:30](Cl)=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)C>[C:22]1([CH2:28][CH2:29][CH2:30][N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc([C@@H]2CCCNC2)c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc([C@@H]2CCCN(CCCc3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of 1.0 g (5.2 mmole) of the (S)(+)-3-(3-methoxyphenyl)piperidine from Preparation 7, Part B, and 1 ml (7.8 mmole) of triethylamine in 10 ml of toluene, at 0° C., was added, dropwise, a solution of 1.3 g (7.8 mmole) of 3-phenylpropionyl chloride in 5 ml of toluene. The reaction mixture was then allowed to warm to room temperature and stirring was continued for 30 minutes. The reaction mixture was then filtered, and the filtrate was evaporated in vacuo to give a yellow oil. The yellow oil was dissolved in 15 ml of tetrahydrofuran and the resulting solution was added dropwise to a slurry of 910 mg (24 mmole) of lithium aluminum hydride in 15 ml of tetrahydrofuran. The resulting mixture was heated under reflux for 2 hours and then it was cooled in an ice-bath. To the cooled mixture was added, dropwise, with stirring, 5 ml of 3% sodium hydroxide, followed by 20 ml of diethyl ether. Stirring was continued for 15 minutes, and then the mixture was filtered. The filtrate was evaporated in vacuo. The residue was dissolved in toluene and evaporated in vacuo several times. This afforded 1.8 g of material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](O)([C:14]([F:17])([F:16])[F:15])=O>Cl>[F:15][C:14]([F:17])([F:16])[C:12]1[NH:11][C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Product: O=C(O)c1ccc2[nH]c(C(F)(F)F)nc2c1
Temperature: 0 °C

Procedure:
50 g (0.329 mol) of 3,4-diaminobenzoic acid, dissolved in 300 ml of 4N HCl, are heated under reflux with 40.5 g (0.355 mol) of TFA for 5 hours. The solution is then cooled to 0° C., and the precipitated product is filtered off with suction, washed with water and dried at 40° C. in vacuo.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(C2C=CC(NC3C=CC=CC=3)=CC=2)=CC=1.[O:30]=[C:31]1[O:37][C@H:36]([C@H:38](CO)O)[C:34]([O-])=[C:32]1O.[Na+]>C(O)(C)(C)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([N:8]1[CH:34]=[C:32]([C:31]([O:37][CH2:36][CH3:38])=[O:30])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(Cc2ccccc2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A solution of benzyl azide (0.200 mL; 1.61 mmol), ethyl propriolate (0.163 mL; 1.61 mmol), copper sulfate pentahydrate (0.016 mL, 1M solution in water), sodium ascorbate (0.161 mL; solution 1M in water) in a mixture of tert-butanol (3 mL) and water (3 mL) was stirred at room temperature overnight. The reaction mixture was diluted in water and the product crystallized out to furnish 0.090 g (24%) of ethyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:25])[N:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16])=[O:4].[N-:26]=[N+:27]=[N-:28].[Na+].[I-].[Na+]>CC(C)=O>[N:26]([CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:25])[N:10]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:11]2=[O:16])=[O:4])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 90.8 %

Procedure:
A mixture of 2-chloro-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.3 g, 3.57 mmol), sodium azide (0.3 g, 4.65 mmol) and sodium iodide (0.54 g, 3.57 mmol) in acetone (50 ml) was refluxed for 17 hours. The solvent was removed in vacuo and the residue was dissolved in EtOAc (60 ml). The EtOAc solution was washed with H2O (30 ml), brine (30 ml), and dried (MgSO4). The solvent was removed in vacuo to give 2-azido-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.2 g, 90%) as a white solid: 1H NMR (CDCl3) δ d 8.48 (s, 1H), 7.84-7.68 (m, 3H), 7.51 (t, J=6.3 Hz, 1H), 5.04-4.97 (dd, J=4.7 and 11.8 Hz, 1H), 4.80 (d, J=6.5 Hz, 2H), 3.97 (s, 2H), 2.95-2.74 (m, 3H), 2.20-2.15 (m, 1H).
Reaction SMILES: CI.[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:32])[C@@H:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:21]SC)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)[CH3:4].[H-].[Na+].CN(C=O)C.[Cl-].[NH4+]>C(Cl)Cl>[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][C@H:19]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]3=[O:32])[CH2:13][CH2:12]2)=[N:9][CH:10]=1)[CH3:4]
Reactant: CCc1cnc(N2CCC(NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C)CC2)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(N3CC[C@H](NC(=O)OC(C)(C)C)C3=O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.3 %

Procedure:
To a solution of (S)-tert-butyl 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-ylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate methyliodide (7 g, 12 mmol) in CH2Cl2 (70 mL) was added 60% NaH in oil (580 mg, 14 mmol). After 5 minutes, DMF (7 mL) was added and the mixture stirred at ambient temperature for 1 hour. The mixture was poured into saturated ammonium chloride (70 mL) and the solution was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was triturated with ether (100 mL) and the ether layer was washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to yield (S)-tert-butyl 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylcarbamate (3.2 g, 8.2 mmol, 68%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH2:4][CH2:3]1.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>>[NH2:14][C:15]1[C:16]([C:17]#[N:18])=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])[CH2:6][CH2:7]1
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)C(=O)NC1CCC(O)CC1
Product: CC(C)C(=O)NC1CCC(Oc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22b from N-(4-hydroxycyclohexyl)isobutyramide (Example 40c) and 2-amino-6-fluorobenzonitrile as an off-white solid (99%). MS 302 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C=O)C.O>[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(Br)C(=O)OCC
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a solution of diethyl malonate (8.01 g; 50 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added potassium carbonate (7.6 g; 55 mmol), which has been dried at 120° C. for 12 h before using. After stirring for 15 min at room temperature, ethyl 2-bromovalerate (8.53 mL; 50 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was poured in water (240 mL) and neutralized by adding a solution of hydrochloric acid 6N. The product was extracted with diethyl ether (2x240 mL) and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by distillation under reduced pressure furnished 12.8 g (99%) of the title compound as a colorless liquid (bp. 117° C., 2 mbar, temperature of the oil bath 165° C.).