Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][NH:47][CH2:48][CH:41]1[CH2:42][O:43][CH2:44]2)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][N:47]([C:20]([C:19]3[CH:18]=[N:17][C:16]([NH:15][C:12]4[N:13]=[CH:14][C:9]5[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)[C:10]=5[N:11]=4)=[CH:24][CH:23]=3)=[O:21])[CH2:48][CH:41]1[CH2:42][O:43][CH2:44]2)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5COCC(C4)N5C(=O)OCc4ccccc4)cn3)nc2n1C1CCCC1
Yield: 80.3 %

Procedure:
Following general amide formation method 3, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (406 mg, 1.03 mmole) was combined with 3-Oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (266 mg, 0.9 mmole) which gave 7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (0.466 g, 0.723 mmol) in 80% yield. MS m/z 639.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:14]([CH2:18][CH2:19][NH2:20])[N+:15]([O-:17])=[O:16].C(OC(C)C)(C)C>>[O:14]([CH2:18][CH2:19][NH:20][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])[N+:15]([O-:17])=[O:16]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)c1ccc(Br)o1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])c1ccc(Br)o1
Yield: 22.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.68 g of 5-bromo-2-furancarboxylic acid and 0.60 g of nitroxyethylamine nitrate, 0.22 g of the title compound was obtained as pale yellow acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[F:21].CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([CH:16]2[O:10][CH2:9][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)=[CH:14][C:13]=1[F:21]
Reactant: CCCCCC(CO)CO
Reactant: O=Cc1cc(F)c(Br)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCC1COC(c2cc(F)c(Br)c(F)c2)OC1
Yield: 35.3 %

Procedure:
10.8 g (0.074 mol) of 2-pentylpropane-1,3-diol, 16.3 g of 4-bromo-3,5-difluorobenzaldehyde and 0.7 g of TsOH were dissolved in 74 cm3 of dichloromethane, and was refluxed for 3 hours on a hot water bath with a Dean-Stark trap applied to remove the water formed. The reactant was washed in water, the dichloromethane was removed, and the residue was recrystallized from a mixture of acetone and methanol to obtain 9.1 g (0.026 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-pentyl-1,3-dioxane.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:4]1.C(N(CC)C(C)C)(C)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].CCOC(C)=O>CN(C=O)C>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[S:12][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]=1[S:7]([N:5]1[CH2:6][CH:3]([CH2:2][NH:1][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:4]1)(=[O:8])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: NCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Reaction time: 18 h
Yield: 19.9 %

Procedure:
To a stirring mixture of Example 2 (200 mg, 0.39 mmol) and N,N-diisopropyl-ethylamine (68 μL, 42 mmol) in DMF (5 mL) was added ethyl bromoacetate (43 μL, 0.39 mmol) and the mixture allowed to stir for 18 hours. After this time EtOAc (25 mL) was added to the reaction mixture which was then washed with brine (3×25 mL), dried (sodium sulfate) and then reduced in vacuo. The resulting oil was purified by column chromatography (SiO2, 50% DCM in EtOAc) to afford the title compound as a white solid (47 mg, 20%). LCMS (pH 3) RT 2.24 minutes, (ES+) 605 (M+H).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.Br[CH2:66][C:67]([C:69]1[CH:74]=[CH:73][C:72]([C:75]#[N:76])=[CH:71][CH:70]=1)=[O:68].CC([O-])(C)C.[Na+]>CS(C)=O>[O:68]1[CH2:66][C@@H:67]1[C:69]1[CH:74]=[CH:73][C:72]([C:75]#[N:76])=[CH:71][CH:70]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CS(C)=O
Product: N#Cc1ccc([C@H]2CO2)cc1
Temperature: 40 °C
Yield: 88.8 %

Procedure:
To 800 mL of 0.2M, pH 6.0 sodium phosphate buffer in a 2 L flask equipped with an overhead stirrer was added D-glucose (38.6 g, 1.2 eq), β-nicotinamide adenine dinucleotide, free acid (1.6 g, mmol), glucose dehydrogenase (36 mg, 3.2 kU, CODEXIS® GDH-102, 90 U/mg), and enzyme KRED-NADH-110 (200 mg, CODEXIS®, 25 U/mg). The vessels containing the reagents above were rinsed with 200 mL of fresh sodium phosphate buffer and added to the reaction which was stirred to dissolution and then heated to 40° C. To this mixture was added a solution of 2-bromo-4′-cyanoacetophenone (40 g, 178.5 mmol) in 100 mL DMSO through an addition funnel in about 30 min. The container was rinsed with 20 mL DMSO and the rinse was added to the reactor. A pH of 5.5-6.0 was maintained by adding 1 M NaOH through a fresh addition funnel (total volume of 200 mL over 6 h) after which HPLC showed complete consumption of the starting material. The reaction mixture was extracted with 800 mL MTBE×2 and the combined extracts were washed with 300 mL of 25% brine. The crude alcohol was transferred to a 3 L 3-neck flask and treated with solid NaOtBu (34.3 g, 357 mmol) stirring for 1 h and then additional NaOtBu (6.9 g, 357 mmol) and stirring for 30 min. The reaction mixture was filtered and the solution was washed with 300 mL 0.2 M pH 6.0 sodium phosphate buffer, brine, and then the solvent was removed in vacuo and the resulting white solid was dried in a vacuum oven to give (S)-4-(oxiran-2-yl)benzonitrile (23 g, 90% yield, 100% e.e.). 1H NMR (400 MHz, CDCl3) δ ppm 7.62 (2H, d), 7.35 (2H, d), 3.88 (1H, dd), 3.18 (1H, app t), 2.73 (1H, dd) Purity=99%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:25][C:26]1[N:31]=[C:30]([NH:32]C(=O)C(F)(F)F)[CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[NH2:32][C:30]1[N:31]=[C:26]([CH2:25][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[C:11]([C:9]([C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[O:10])=[CH:12]2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Nc1cccc(CBr)n1)C(F)(F)F
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3cccc(N)n3)c3ccccc3c2=O)cnc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 75 mg (0.27 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one, 13 mg (0.32 mmol) of 60% sodium hydride, 92 mg (0.32 mmol) of N-(6-bromomethyl-pyridin-2-yl)-2,2,2-trifluoro-acetamide and 0.7 mL of N,N-dimethylformamide. Yield: 20 mg of a white solid: LC-MSD, m/z for C23H20N4O2 [M+H]+=385.1; HPLC retention time: 0.3 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][C:5]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)([O-])=O.S1C=CC=C1.O1CCCC1>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][C:5]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(COC2CCCCO2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc(C(=O)c2ccccc2)cc1COC1CCCCO1
Yield: 82 %

Procedure:
A mixture of 20 parts of intermediate 56, namely [4-nitro-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]phenyl] phenylmethanone, 2 parts of a solution of thiophene in methanol 4% and 395 parts of methanol was hydrogenated overnight at normal pressure and room temperature with 2 parts of palladium-on-charcoal catalyst 10%. Tetrahydrofuran was added to dissolve the precipitated reaction product. The catalyst was filtered off and the filtrate was evaporated. The residue was recrystallized from methanol. The product was filtered off, washed with methanol and 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 14.93 parts (82.0%) of [4-amino-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methy]phenyl] phenylmethanone; mp. 164.0° C. (interm. 57).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:17][C:16](=[O:18])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[F:25][C:21]1[CH:20]=[C:19]([N:15]2[CH2:14][C@H:13]([CH2:12][N:26]=[N+:27]=[N-:28])[O:17][C:16]2=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(c3cccc(F)c3)C(=O)O2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reaction time: 8 h

Procedure:
A mixture of (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl 4-methylbenzenesulfonate (PREPARATION 15, 2.340 g, 6.40 mmol) in dry DMF (60 ml) is treated with solid sodium azide (3--331 g, 51.23 mmmol) at 20°-25°. The resultant slurry is warmed to 65° for 4.5 hr and then cooled to 20°-25° and left overnight. The reaction mixture is then diluted with ethyl acetate and water, transferred to a separatory funnel, and extracted with ethyl acetate. The combined ethyl acetate extracts are washed thoroughly with water, and then dried (sodium sulfate), filtered and concentrated under reduced pressure to give the title compound. mp 81°-82°; [α]25D 136.5° (c 0.9, CHCl3); IR (mineral oil mull): 2115, 1736, 1614, 1591, 1586. 1497, 1422, 1233, 1199, 1081, 1049 cm-1 ; NMR (CDCl3, 300 MHz) δ 7.45, 7.34, 7.23, 6.86, 4.81, 4.09, 3.86, 3.72 and 3.60; MS (m/z) 236 (59.0, M+), 179, 136, 122, 109, 95, 75; HRMS (m/z) 236.0708 (calc'd for C10H9FN4O2 : 236.0709).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.CN.[C:19]([BH3-])#[N:20].[Na+].[OH-].[K+]>[Cl-].[Zn+2].[Cl-].CO>[NH2:20][CH2:19][CH:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: [BH3-]C#N
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Agent: CN
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: NCC1C2CCN(CC2)C1Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (2.16 g, 0.01 mol), methylamine (25 mL, 0.05 mol) and zinc chloride (5 mL, 0.005 mol) were added to dry methanol (30 mL) and stirred at room temperature for 30 min. Then, sodium cyanoborohydride (30 mL, 1.0M in THF) was added carefully and the mixture stirred at room temperature for 48 h. The mixture was adjusted to pH 10 using 2N potassium hydroxide and then the solvent was removed by rotary evaporation. The residue was extracted with chloroform (3×50 mL), dried (MgSO4), filtered and concentrated by rotary evaporation to yield the crude desired amine as a light yellow oil (2.40 g, 83% yield). The product was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[CH:7]=[CH:6][C:5]=1[Cl:11].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C(N(CC)CC)C.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(I)ccc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1Cl
Yield: 98.1 %

Procedure:
A mixture of 2-chloro-5-iodo-benzoic acid methyl ester (3.5 g, 12 mmol), dichlorobis(triphenylphosphino)palladium (II) (0.04 g, 0.06 mmol), triphenylphosphine (0.06 g, 0.24 mmol), copper iodide (0.05 g, 0.24 mmol), (trimethylsilyl)acetylene (1.9 g, 19.2 mmol) in triethylamine (40 mL) was heated at reflux for 12 h. The mixture was concentrated in vacuo, diluted with ethyl acetate (150 mL) and washed sequentially with 10% aqueous citric acid, water, and brine. The organic solution was dried, filtered and concentrated in vacuo to afford the title compound (3.14 g).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11]1.F[C:27]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=1[C:29]#[N:30].[Cl-].[NH4+]>CO.[C].[Pd].C(OCC)C.O1CCCC1>[C:29]([C:28]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:27]=1[O:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)#[N:30]
Reactant: O=C(OCc1ccccc1)N1CCN(CCO)CC1
Reactant: N#Cc1cc(F)ccc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: N#Cc1cc(F)ccc1OCCN1CCNCC1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Under nitrogen atmosphere, potassium tert-butoxide (869 mg) was added to a tetrahydrofuran solution (10 ml) of benzyl 4-(2-hydroxyethyl)-1-piperazinecarboxylate (1.86 g) in an ice bath. After stirring for one hour, the reaction system was transferred to a dry ice-methanol bath, and after 10 minutes, a 2,5-difluorobenzonitrile (1.09 g)/tetrahydrofuran solution (5 ml) was added thereto. After stirring for 2 hours while the temperature of the reaction system was naturally returned to a room temperature, an aqueous saturated ammonium chloride and diethyl ether were added thereto, to separate the organic layer. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate system), to give a colorless oil as an intermediate (1.10 g, 46%). The intermediate (1.10 g) was dissolved in methanol (10 mL), 10% palladium carbon (100 mg) was added, and the mixture was stirred at room temperature under hydrogen atmosphere. After 1.5 hours, the reaction catalyst was filtered through Celite, and the filtrate was evaporated. The resulting title compound (647 mg, 80%) obtained was used for the next reaction as it was.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-].Cl>C(Cl)Cl.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([NH2:26])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: [NH4+]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(OCc2ccccc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirred solution of 5-(benzyloxy)-2-methoxybenzoic acid (8, 1.16 g. 4.5 mmol) in CH2Cl2 (25 mL) at room temperature was added oxalyl chloride (1.5 mL, 17.9 mmol). The reaction mixture was stirred at room temperature for 2 h. It was concentrated to dryness to provide the crude acid chloride as a brown-yellow waxy solid. The crude acid chloride was dissolved in THF (10 mL) and was added dropwise to a stirred mixture of concentrated NH4OH (20 mL) and THF (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h and was adjusted to pH 8 with 2 N HCl. The precipitate was collected, washed with water, and dried in vacuo to afford the title compound (0.73 g, 63%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=3.3 Hz, 1H), 7.82 (br s, 1H), 7.47-7.43 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.30 (m, 1H), 7.10 (dd, J=9.0, 3.3 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 5.75 (br s, 1H), 5.08 (s, 2H), 3.94 (s, 3H); ESI MS m/z 258 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH:12]([CH3:17])[CH2:13][C:14](O)=[O:15])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH3:1][C:2]1[C:10]([C:11]2[CH:12]([CH3:17])[CH2:13][C:14](=[O:15])[NH:20][N:21]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: NN
Reactant: Cc1nn2ccccc2c1C(=O)C(C)CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1nn2ccccc2c1C1=NNC(=O)CC1C
Yield: 75.1 %

Procedure:
The compound (2.76 g) of Example 17 and hydrazine monohydrate (0.90 g) were dissolved into ethanol (30 ml), and the solution was refluxed for 3 hours under heat. The reaction liquor was submitted to distillation under reduced pressure, and the residue was purified by means of silica gel column chromatography (developing solvent, methylene chloride:ethanol=10:1) to obtain aimed product (2.04 g) as colorless powder. When recrystallizing from isopropyl ether, this gave colorless prismatic crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[N:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]2)(=[O:16])=[O:17])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)N2CCN(CC)CC2)cnc1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinoate (10.2 g, 0.0275 mol) was dissolved in toluene (50 mL) and a solution of sodium hydroxide (1.1 g, 0.0275 mol) in water (20 mL) added to it. This two phase mixture was then stirred vigorously at ambient temperature overnight. The aqueous phase was separated off and adjusted to pH=5.6 by addition of c. hydrochloric acid. The precipitated product was slurried with ice cooling for 15 minutes, filtered, water washed and dried under vacuo at 50° C. to afford the title compound as an off-white solid. Mpt 206–207° C. δ (CDCl3): 1.25 (3H, t), 1.39 (3H, t), 2.82 (2H, q), 3.03 (4H, m), 3.25 (4H, m), 4.50 (2H, q), 8.25 (1H, d), 8.56 (1H, d). m/z (Found:344 [M+H]+, 100%. C14H22N3O5S requires 344.38).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([N:30](C)[C:31](=O)OC(C)(C)C)[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([C@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([NH:30][CH3:31])[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1cc(C)ccc1F)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-5-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (49 mg, 88.2 μmol, Eq: 1.00) was combined with DCM (3 mL) to give a colorless solution. TFA (1.00 mL, 13.0 mmol, Eq: 147) was added. The reaction was stirred at rt for 1 h and then concentrated in vacuo. The residue taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)-1-[(S)-3-Methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-fluoro-5-methyl-phenyl)-amide as a white foam (37 mg), m/z=456 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:18][C:19]([O:22][C:23]([NH:25][C@H:26]([C:33](O)=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])([CH3:21])[CH3:20]>>[C:19]([O:22][C:23](=[O:24])[NH:25][C@H:26]([C:33](=[O:34])[N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:21])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: Cc1ccc(NCCc2cccnc2)cc1C
Product: Cc1ccc(N(CCc2cccnc2)C(=O)[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)cc1C

Procedure:
In analogy to the procedure described for the synthesis example 21, step 3, the title compound was prepared from (3,4-dimethyl-phenyl)-(2-pyridin-3-yl-ethyl)-amine and boc-L-alpha-phenylglycine. MS (m/e): 460.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[N:10]=[N:9]1.[C:26](C1CCN(C(OC(C)(C)C)=O)CC=1)#CC>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:26])=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3Cl)nn2)CC1
Reactant: CC#CC1=CCN(C(=O)OC(C)(C)C)CC1
Product: Cc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1Cl

Procedure:
The same operation as in Example 7 was carried out using the azide compound prepared in Example 1 and tert-butyl 4-(1-propynyl)-1,2,3,6-tetrahydropyridine-1-carboxylate prepared in 3) of Example 7 to give the title compound as a white solid.
Reaction SMILES: [CH2:1](OC1C=CC(Cl)=CC=1C(Cl)=O)[CH:2]=C.[CH2:15]([O:18][C:19]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=1)=[O:22])[CH:16]=C.C(OC1C=CC(Cl)=CC=1C(NCCC1C=CC(CC(O)=O)=CC=1)=O)C=C>>[CH2:15]([O:18][C:19]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:20]=1[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=1)=[O:22])[CH2:16][CH2:1][CH3:2]
Reactant: C=CCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)OCC)cc1
Reactant: C=CCOc1ccc(Cl)cc1C(=O)Cl
Agent: C=CCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)O)cc1
Product: CCCCOc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
with 2-allyloxy-5-chlorobenzoyl chloride, via ethyl 4-[2-(2-allyloxy-5-chlorobenzamido)-ethyl]-phenylacetate, 4-[2-(2-allyloxy-5-chlorobenzamido)-ethyl]-phenylacetic acid; m.p. 104°-105° C., after recrystallization from ethyl acetate.