Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)CCC=C.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[F:32]>>[CH2:19]([Si@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)[CH2:24][CH:23]=[CH:22][CH3:21]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: C=CCCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Product: CC=CCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 34.1 g of 4-(4-(4-pentenyl)-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.CCCCC.C([Li])(C)(C)C.CN(C)[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[CH:28]([C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:15])([CH3:14])[CH3:1])=[O:29]
Reactant: C[Si](C)(C)CCOCOc1cccnc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cnccc1C=O
Temperature: -70 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (39.3 g, 0.174 mol) in tetrahydrofuran (250 ml), a 1.47 mol/L t-butyllithium n-pentane solution (154 ml, 0.227 mol) was added dropwise at −70° C. over 40 minutes. After stirring at −70° C. for 1 hour, N,N-dimethylformamide (40 mL, 0.522 mol) was added over 30 minutes and stirred at −70° C. for 1.5 hours. After warming to −20° C., saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give 4-formyl-3-[2-(trimethylsilyl)ethoxymethoxy]pyridine (24.5 g, 58%) as a brown oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=O)=[CH:28][CH:27]=4)[N:20]=3)=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1>C1COCC1.O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([CH2:32][N:34]5[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]5)=[CH:30][CH:31]=4)[N:20]=3)=[CH:17][NH:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: CN1CCN(C(=O)c2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the suspension of 96 mg (2.53 mMol; 4 Eq.) of lithium aluminum hydride (Fluka 62420) in 20 mL of THF abs. under Argon at rt is added slowly within 10 min 300 mg (0.633 mMol) of (4-{4-([3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-ylamino}-phenyl)-(4-methyl-piperazin-1-yl)-methanone (see Example 31) as a solid; under vigorous foaming. After stirring for 2.5 h at rt, the suspension is cooled to 0° C. and treated dropwise with 20 mL of water. After diluting further with 50 mL of water, the suspension is extracted with ethyl acetate. The combined organic layers are washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product is purified over silica gel, eluting with CH2Cl2/CH3OH (4:1) followed by trituration in diethyl ether to obtain {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[C:8]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)[CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1(C(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)CCNC[CH2:39]1.B(O)O>>[C:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[C:8]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]4)=[O:31])=[CH:28][CH:29]=3)[CH:23]=2)[CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Agent: OBO
Product: CN1CCN(C(=O)c2ccc(-c3cncc(-c4cc(NC(C)(C)C)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
The title compound is prepared analogously to [4-(6′-tert-Butylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenyl]-piperazin-1-yl-methanone (Example 2.48) by replacing piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone with the appropriate boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[C:9]([Br:19])=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
A solution of 2-amino-isonicotinic acid methyl ester (5.58 g, 36.7 mmol) in DMF (56 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (7.21 g, 38.5 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (500 mL) and washed with water (2×250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (3.0 g, 13.0 mmol, 35%) as a yellow solid, which was used in the next step without further purification. MS: 231 [M+1]+; HPLC: AtRet=0.70.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([O:17][CH:18]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=O)=[C:11]2[CH:10]=[N:9]1.[Cl-].[NH4+].CC[N:38](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([O:17][CH:18]([CH2:19][CH2:20][C:21]([NH2:38])=[O:23])[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=3)=[O:25])=[C:11]2[CH:10]=[N:9]1
Reactant: Cc1ccc(NC(=O)C(CCC(=O)O)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)C(CCC(N)=O)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Reaction time: 0.75 h
Yield: 58.5 %

Procedure:
A solution of 4-{[1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}-5-[(5-methylpyridin-2-yl)amino]-5-oxopentanoic acid (5.0 mg, 0.011 mmol), ammonium chloride (3.0 mg, 0.054 mmol), DIPEA (7.0 mg, 0.054 mmol) and TBTU (7.0 mg, 0.021 mmol) in THF (1 mL) was stirred at ambient temperature for 3 hrs. Water (1 mL) was added and the reaction mixture was purified by preparative HPLC: Mobile phase A: 100% ACN, Mobile phase B: 5% ACN+95% 0.1M NH4OAc in water; Gradient: 0% A to 50% A over 45 min; Flow: 25 ml/min; UV: 235 nm, to give the title compound (3.0 mg). 1H NMR (500 MHz, CDCl3) δ 9.18 (br s, 1H), 8.59 (s, 1H), 8.42 (s, 1H), 8.16 (d, 1H), 8.09 (s, 1H), 7.64 (m, 1H), 7.53 (m, 4H), 5.94 (s, 1H), 5.75 (br s, 1H), 5.57 (br s, 1H), 2.58 (m, 4H), 2.32 (s, 3H), HRMS: calcd for (M+H+) C22H2135ClN7O3: 466.1394. Found: 467.1426.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[C@H:8]2[C@@H:4]1[C@H:5]([O:10]CC1C=CC=C(OC3C=CC=CC=3)C=1)[O:6][C:7]2=[O:9]>CC(C)=O>[CH3:2][C:3]1([CH3:25])[C@H:4]2[C@@H:8]1[C@H:7]([OH:9])[O:6][C:5]2=[O:10]
Reactant: CC1(C)[C@H]2[C@H](OCc3cccc(Oc4ccccc4)c3)OC(=O)[C@H]21
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)[C@H]2[C@H](O)OC(=O)[C@H]21
Temperature: 20 °C
Reaction time: 4 h
Yield: 102 %

Procedure:
8 ml of 0.5N aqueous hydrochloric acid were slowly added to a solution of 0.805 g of the product of Example 9 melting at 82° C. in 8 ml of acetone and the mixture was stirred at 20° C. for 4 hours. The aqueous phase was extracted with petroleum ether and the aqueous phase was evaporated to dryness under reduced pressure to obtain 0.360 g of (1R,4R,5S)(-)6,6-dimethyl-4-hydroxy-3-oxabicyclo(3,1,0)hexan-2-one melting at 116° C. and having a specific rotation of [α]D20 =-114°±1.5° (c=1% in dimethylformamide).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:15][C:14]=1[N:35]=S(C)C.CSC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:12][C:13]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][C:22](=[O:28])[N:23]([CH:25]([CH3:27])[CH3:26])[N:24]=2)[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:15][C:14]=1[N:35]=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)n1nc(-c2nc(Br)c(N=S(C)C)nc2-c2ccccc2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Product: CC(C)n1nc(-c2nc(Br)c(N=O)nc2-c2ccccc2)ccc1=O
Reaction time: 1 h
Yield: 49.7 %

Procedure:
To a solution of m-chloroperbenzoic acid (70-75% purity) (1.66 g) in CH2Cl2 (40 ml) was added a solution of 6-{6-bromo-5-[(dimethyl-lambda˜4˜-sulfanylidene)amino]-3-phenyl-2-pyrazinyl}-2-isopropyl-3 (2H)-pyridazinone (2.01 g) in CH2Cl2 (20 ml) at −10˜-5° C. and the mixture was stirred at the same temperature for one hour. After addition of dimethyl sulfide (0.25 ml), the solution was stirred at the same temperature for 30 minutes. Sat. aq. Na2CO3 (50 ml) was then added to the mixture. An organic layer was collected, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (70:30 v/v) to give 6-(6-bromo-5-nitroso-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone as a solid (0.896 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([OH:25])=O)[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:41](=[O:57])([O:43][CH2:44][CH:45]([NH2:56])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53])[NH2:42].Cl>CN(C=O)C>[C:41](=[O:57])([O:43][CH2:44][CH:45]([NH:56][C:23](=[O:25])[CH2:22][N:10]1[C:11](=[O:21])[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:53])[F:54])[NH2:42]
Reactant: NC(=O)OCC(N)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A quantity of 30 mg (0.08 mmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (preparation according to WO2007/134862, Example 154A) was dissolved in 1 ml of DMF, and the solution was admixed with 21 mg (0.11 mmol) of EDC and with 15 mg (0.11 mmol) of HOBt and subsequently stirred at room temperature for 20 minutes. Then 23 mg (0.09 mmol) of the compound from Example 180A were added and the mixture was left with stirring at room temperature for 16 h. For work-up, 50 μl of 1N hydrochloric acid were added and the crude product was purified directly by preparative HPLC [Method 19]. This gave 34 mg (69% of theory) of the target compound.
Reaction SMILES: [C:1]([C:3]1[CH2:4][O:5][CH2:6][CH:7]=1)#[N:2].C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:22]([N:29]([CH2:35]OC)[CH2:30][Si](C)(C)C)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([N:29]1[CH2:30][C:3]2([C:1]#[N:2])[CH:7]([CH2:6][O:5][CH2:4]2)[CH2:35]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: N#CC1=CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC12COCC1CN(Cc1ccccc1)C2

Procedure:
A solution of 5.2 g (24.6 mmol, 46% strength) of 3-cyano-2,5-dihydrofuran in 50 ml of absolute methylene chloride is mixed with 0.3 g of triethylamine and 0.3 g of trifluoroacetic acid, the mixture is heated under reflux and then 7 g (29.5 mmol) of N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)-amine are added dropwise. Subsequently, the mixture is heated under reflux for 2 hours and the solution is washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulphate, concentrated and distilled. Yield: 4.5 g (80% of theory). Boiling point: 140°-145° C./0.03 mbar
Reaction SMILES: C1(OC(N2C[C@@H](P(C3C=CC=CC=3)C3C=CC=CC=3)C[C@H]2CP(C2C=CC=CC=2)C2C=CC=CC=2)=O)C=CC=CC=1.[CH:42](=[C:49]([CH2:53][C:54]([N:56]1[CH2:64][C@H:63]2[C@H:58]([CH2:59][CH2:60][CH2:61][CH2:62]2)[CH2:57]1)=[O:55])[C:50]([OH:52])=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH:46]1[CH:45]=[CH:44][C:43]([CH2:42][C@H:49]([C:50]([OH:52])=[O:51])[CH2:53][C:54]([N:56]2[CH2:57][C@H:58]3[C@H:63]([CH2:62][CH2:61][CH2:60][CH2:59]3)[CH2:64]2)=[O:55])=[CH:48][CH:47]=1
Reactant: O=C(O)C(=Cc1ccccc1)CC(=O)N1C[C@H]2CCCC[C@H]2C1
Agent: O=C(Oc1ccccc1)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@H]1CP(c1ccccc1)c1ccccc1
Product: O=C(O)[C@H](CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccccc1

Procedure:
The preparation was carried out in the same manner as in Example 1, except that 3.02 mg of (2S,4S)-N-phenyloxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine (PPPM) was used instead of 3.02 mg of PCPPM of Example 1. After the reaction, the residual ratio of 2-benzylidene-3-(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid was 9.74%, and the optical purity of mitiglinide thus obtained was 94.5% e.e.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[NH:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Br:27])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:33].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]([C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Br:27])[CH:21]=1)[CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1NC(=O)c1ccc(Cl)c(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(OCCCC(=O)OC(C)(C)C)c1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a solution of 4-[2-(3-bromo-4-chloro-benzoylamino)-3-methyl-phenoxy]-butyric acid tert-butyl ester (10.2 g, 21.3 mmol) in dry DMF (100 mL) at 0° C. under N2, NaH (60% in mineral oil, 1.7 g, 42.6 mmol) was added in several portions with stirring. 10 minutes later, iodomethane (2.0 mL, 32.1 mmol) was added. The mixture was warmed to room temperature by removal of ice bath and stirring was continued for 1 hr. Water (10 mL) was then added and organics were extracted by ethyl acetate, which was then washed by water and brine, and was dried over MgSO4. After concentration, the crude product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1/4) to yield 4-{2-[(3-bromo-4-chloro-benzoyl)-methyl-amino]-3-methyl-phenoxy}-butyric acid tert-butyl ester (9.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22])[CH3:13]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:12][CH3:13])=[O:22]
Reactant: CCc1ccccc1N=C=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: CCc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 45.1 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-ethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethylphenylisocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 43%). EI-MS m/z 302(M+H)+.
Reaction SMILES: [CH:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=1)[CH2:5][C:6]1[N:7](COCC[Si](C)(C)C)[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[N:9]1[CH:10]=[C:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[NH:7][CH:8]=1
Reactant: CC(C)N(Cc1cncn1COCC[Si](C)(C)C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(Cc1cnc[nH]1)c1cccc(N)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Isopropyl-(3-nitro-phenyl)-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-ylmethyl]-amine (0.2 g, 0.51 mmol) was dissolved in ethanol, palladium on charcoal (20 mg, 10% Pd) was added and the mixture was hydrogenated overnight. The catalyst was filtered off and the solvent was evaporated. The residue was dissolved in ethyl acetate and filtered over silica gel. After evaporation the residue was dissolved in hydrochloric acid in ethanol (5M, 1 ml) and stirred at 60° C. for 2 hours. The solvent was evaporated and the residue was partitioned between sodium hydroxide solution (10%) and dichloromethane. After separation the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate/methanol=90:10) to yield a light yellow gum, (0.054 g, 51%); MS (ISP): 231.4 ((M+H)+.).
Reaction SMILES: Cl[CH2:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[C:6]1([S:3]([CH2:2][C:17]2[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=2[N+:19]([O-:21])=[O:20])(=[O:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(F)cc1CS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of chloromethylphenyl sulfone (10.51 g, 55.13 mmol) in THF (110 mL) was added 5.9 mL (56 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was chilled to 0° C., and 1.0 M potassium tert-butoxide in THF (145 mL, 145 mmol) was added dropwise. The reaction mixture was stirred under nitrogen at ambient temperature for one hour. Acetic acid (9 mL, 160 mmol) was then added. The reaction mixture was solvent evaporated and partitioned in brine and ethyl acetate. The organic phase was then dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was stirred in diethyl ether, filtered and dried in vacuo at 73° C. for 12 hours. 2-Benzenesulfonylmethyl-4-fluoro-1-nitrobenzene as a light brown-yellow solid was obtained (10.24 g, 62.8%): MP: 169-171° C.; Mass spectrum (−EI, [M−H]−) m/z 294. 1HNMR (500 MHz, DMSO-d6): δ8.10-8.14 (m, 1H), 7.70-7.75 (m, 1H), 7.56-7.63 (m, 4H), 7.45-7.50 (m, 1H), 7.20 (dd, 1H, J=9.27 Hz and 2.81 Hz), 5.12 ppm (s, 2H). Elemental Analysis for C13H10FNO4S: Calcd: C, 52.88; H, 3.41; N, 4.74; Found: C, 52.63; H, 3.14; N, 4.66;
Reaction SMILES: [C:1]([CH:6]([C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17](C(OCC)=O)[C:16]2=[O:29])=[CH:10][C:9]=1[CH2:30][CH2:31][CH3:32])([O:3]CC)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH:6]([C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:29])=[CH:10][C:9]=1[CH2:30][CH2:31][CH3:32])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Cn2c(=O)[nH]c3ccccc32)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
The product of step D (0.132 g, 0.24 mmol) was suspended in 2.0 mL of methanol and the flask was placed in a sonicator bath until the contents were completely dissolved. Next, 95 μL of a 5.0 N solution of sodium hydroxide were added and the reaction was stirred at room temperature overnight. The reaction mixture was then adjusted to pH=5-6 with dropwise addition of 6 N hydrochloric acid, and then concentrated in vacuo. The residue was redissolved in methanol, filtered, and evaporated. The mixture was then purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH-NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.038 g (35%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:15][CH2:16][C:17]#[N:18]>O1CCOCC1.Cl>[C:16]([CH2:17][NH:18][S:9]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])#[N:15]
Reactant: O=S(=O)(Cl)c1cnccc1C(F)(F)F
Reactant: N#CCN
Agent: Cl
Solvent: C1COCCO1
Product: N#CCNS(=O)(=O)c1cnccc1C(F)(F)F
Reaction time: 8 h
Yield: 28.8 %

Procedure:
4-Trifluoromethyl-pyridine-3-sulfonyl chloride (0.45 g) was dissolved in dioxane (3 ml), and ami-noacetonitrile (1.0 g) was added to the mixture and allowed to stand at ambient temperature overnight. The reaction was diluted with 0.5% HCl and 37% HCl was added dropwise until the mixture became acidic. This was extracted three times with ethyl acetate. The ethyl acetate portions were combined, washed with saturated sodium bicarbonate and dried with magnesium sulfate. The drying agent was filtered away and the solvent evaporated to give 0.14 g of crude 4-Tri-fluoromethyl-pyridine-3-sulfonic acid cyanomethyl-amide, which was chromatographed an silica gel using methylene chloride to yield 0.06 g of purified 4-Trifluoromethyl-pyridine-3-sulfonic acid cyanomethyl-amide. LC/ms analysis with RT=1.12 min yielded a purity of 99% m+/m− of 265.87/263.88. Melting point of the purified compound tested as 158-159° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:4]=1.[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20](Cl)[C:19]([Cl:26])=[CH:18][N:17]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[C:20]([N:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:5]3[N:4]=[C:3]([CH3:2])[O:7][N:6]=3)[CH2:14][CH2:13]2)[C:19]([Cl:26])=[CH:18][N:17]=1
Reactant: Cc1nc(CN2CCNCC2)no1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)no1
Temperature: 45 °C
Yield: 70.2 %

Procedure:
1-[(5-Methyl-1,2,4-oxadiazol-3-yl)methyl]piperazine hydrochloride (217 mg, 0.99 mmol) and 2-amino-4,5-dichloro-3-nitropyridine (208 mg, 1.0 mmol) were stirred in 2-propanol (5 mL) and diisopropylethylamine (523 μL, 387 mg, 3.0 mmol) was added. The mixture was stirred and heated at 45° C. for 23 h. The reaction was cooled and the product filtered off and washed with 2-propanol. Drying in vacuum gave the product (246 mg, 69%). 1H-NMR (500 MHz, CDCl3), 2.63 (s, 3H, CH3), 2.77 (br m, 4H, piperazine C—H), 3.29 (m, 4H, piperazine C—H), 3.76 (s, 2H, CH2), 5.27 (s, 2H, NH2), 8.02 (s, 1H, pyridine 6-H).