Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Reactant: Fc1ccccn1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccccn2)CC1

Procedure:
A stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.15 g, 0.61 mmol, Example 30B) and 2-fluoropyridine (0.3 mL, 3.5 mmol) was heated to 175° C. under microwave conditions for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by chromatography (silica gel, eluting with 20% to 35% ethyl acetate in hexane) to provide (4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 326 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.06 (dd 1H), 7.52 (m, 1H), 7.37-7.26 (m, 5H), 6.80 (d, 1H), 6.62 (t, 1H), 5.04 (s, 2H), 4.84 (s, 1H), 3.78 (m, 2H), 3.25-3.16 (m, 2H), 2.08 (m, 2H), 1.64-1.55 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: C([O:8]/[N:9]=[C:10]1\[CH2:11][CH2:12][C:13]2[C:18]\1=[CH:17][CH:16]=[C:15]([C:19]1[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[N:21][N:22]([CH2:24][CH2:25][OH:26])[CH:23]=1)[CH:14]=2)C1C=CC=CC=1.Cl.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:26][CH2:25][CH2:24][N:22]1[CH:23]=[C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:10](=[N:9][OH:8])[CH2:11][CH2:12]3)[C:20]([C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[N:21]1
Reactant: [H][H]
Reactant: OCCn1cc(-c2ccc3c(c2)CC/C3=N\OCc2ccccc2)c(-c2ccncc2)n1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: OCCn1cc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To (E)-5-(1-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one O-benzyl oxime (31.9 mg; Example 4, Step 4) in 5 mL methanol was added 38 μL 6M hydrochloric acid and about 5 mg palladium hydroxide (20% by weight on carbon). A hydrogen-filled balloon was attached to the reaction vessel and the mixture was stirred at ambient temperature for 1 hour. The mixture was filtered through celite, the celite was washed with methanol, and the filtrate treated with a small amount of saturated aqueous sodium bicarbonate. The filtrate was concentrated under vacuum and the residue was purified by chromatography, eluting with a 10:1 mixture of dichloromethane-methanol to yield 13.2 mg (53% yield) of a white solid. 1H NMR (CDCl3) was consistent with the desired structure 110. LC/MS showed one peak with a M+1 molecular ion of m/z 335.4 by positive ESI.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 4-bromo-2-chlorobenzyl alcohol (14.48 g) in N,N-dimethylformamide (72 ml) were added imidazole (5.34 g) and tert-butylchlorodiphenylsilane (19.8 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was applied to silica gel column chromatography (hexane) to give 4-bromo-1-((tert-butyldiphenylsiloxy)methyl)-2-chlorobenzene (29.22 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:19])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C(F)(F)F)nc2ccc(Cl)cc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1nc(Cl)c2cc(Cl)ccc2n1
Yield: 55.2 %

Procedure:
6-Chloro-2-trifluoromethyl-quinazolin-4-ol (1.35 g, 5.43 mmol, 1 eq.), phosphorous oxychloride (4.88 mL, 52.4 mmol, 9.64 eq.) and triethylamine (2.43 mL, 17.4 mmol, 3.21 eq.) were refluxed for 2 hours. Stripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried and stripped in vacuo to give an amber oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 800 mg of off-white solids as product. The product was used immediately in Example 1 Part C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 4-Chloro-5-methyl-2-nitro-phenol (3.752 g, 20.0 mmol), 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.83 g, 24 mmol), and triphenylphosphine (6.23 g, 24 mmol) in 75 mL THF is added diisopropyl asodicarboxylate (4.73 mL, 245 mmol) in several portions at 22° C. for 1 h. The reaction is stirred at the same temperature for an additional 2 hrs. The reaction mixture is concentrated in vacuo. The residue is taken up in 50 mL ether, and let stand at 22° C. for 14 hrs. The resulting crystals are removed by filtration. The filtrate is concentrated in vacuo, and the residue is purified over a 330 g SiO2 column (ISCO) using a gradient of 20 to 40% ethyl acetate in hexanes as eluent, affording 4-(4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as dark yellow viscous oil. MS (ES+); 315.1 (MH+−C4H8), 393.1 (MNa+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]([OH:18])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]([OH:18])=[O:17])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccccc1S
Reactant: Brc1cccc(Br)c1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1Sc1cccc(Br)c1

Procedure:
A mixture consisting of 179 g. m-dibromobenzene (0.758 mole); 46.6 g. thiosalicyclic acid (0.303 mole); 25.9 g cuprous oxide (0.181 mole); 212 cc. quinoline; and 24 cc. pyridine is mechanically stirred and heated in an oil bath at 200° C. to 210° C. for three hours. The internal temperature remains constant at 145° C. The reaction mixture is then poured into 1500 cc. of 5N aqueous HCl. The oily solid is filtered, then dissolved in 750 cc. 1N aqueous NaOH solution; this solution is filtered through celite, then extracted three times with ether. The aqueous fraction is acidified with concentrated HCl and the resulting grayish solid filtered, washed well with water and dried. The crude yield obtained is 65 g. (69.4%). It is used as such in the next step.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:21][CH2:20][C:9]2([O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.O>[C:14]1([C:11]2[CH2:10][C:9]3([CH2:20][CH2:21][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[O:13][N:12]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (190 mg, 0.67 mmol) in MeOH (5 ml) and lithium hydroxide monohydrate (74 mg, 1.0 mmol) in H2O (1 ml) was stirred overnight at RT. After removal of the solvent under vacuum, the residue was taken up in 10% aq. citric acid solution and EtOAc and the phases were separated. The aqueous phase was extracted several times with EtOAc, dried over magnesium sulphate and desolventised under vacuum. 150 g (87% of the theoretical amount) of the free acid 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid was obtained in the form of a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)#[N:14].Cl>O1CCOCC1>[O:9]=[C:7]1[NH:14][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[N:1][C:2]2[S:3][C:4]([CH3:12])=[CH:5][C:6]1=2
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CCOC(=O)c1cc(C)sc1N
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3sc(C)cc3c(=O)[nH]2)cc1
Yield: 119.2 %

Procedure:
5 g of 2-amino-5-methyl-3-ethoxycarbonyl-thiophene is dissolved with 2.7 g of methyl 4-cyanobenzoate in 40 ml of dioxane. Gaseous HCl is then passed through the solution for 5 hours. After customary working up, 6 g of methyl 4-(3,4-dihydro-4-oxo-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoate are obtained.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[F:55][C:56]1[CH:61]=[CH:60][C:59]([C@H:62]([NH:64][C:65]([C@H:67]2[CH2:72][CH2:71][C@H:70]([NH:73][S:74]([C:77]3[CH:82]=[CH:81][C:80]([C:83](=[O:85])[CH3:84])=[CH:79][CH:78]=3)(=[O:76])=[O:75])[CH2:69][CH2:68]2)=[O:66])[CH3:63])=[CH:58][CH:57]=1>C(Cl)Cl.CO>[F:55][C:56]1[CH:61]=[CH:60][C:59]([C@H:62]([NH:64][C:65]([C@H:67]2[CH2:68][CH2:69][C@H:70]([NH:73][S:74]([C:77]3[CH:78]=[CH:79][C:80]([C:83](=[O:85])[CH2:84][Br:1])=[CH:81][CH:82]=3)(=[O:75])=[O:76])[CH2:71][CH2:72]2)=[O:66])[CH3:63])=[CH:58][CH:57]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(C(=O)CBr)cc2)CC1)c1ccc(F)cc1
Reaction time: 28 h

Procedure:
Tetrabutylammonium-tribromide (216 mg, 0.447 mmol) was added to solution of trans-4-(4-acetyl-benzenesulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 104, 194 mg, 0.434 mmol) in DCM/MeOH (2/1, 1.45 ml) at room temperature. The reaction was stirred 16-40 hours, then concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to crude product which was chromatographed on a Biotage 40S column using ethyl acetate/heptane as the eluent to give the title compound (122 mg, 0.232 mmol).
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:27])[CH2:11][CH:12]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[C:38](O)=[O:39].CN1CCOCC1>C(Cl)Cl>[C:21]1([S:18]([CH:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][CH:10]([OH:27])[CH:2]([NH:1][C:38]([C:29]2[CH:30]=[N:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:39])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)CCC(CC(O)C(N)Cc1ccccc1)S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cnc2ccccc2n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of one equivalent of 2-amino-5-benzenesulfonyl-8-methyl-1-phenyl-nonan-3-ol in methylene chloride is added 1.05 equivalents each of 2-quinoxalinecarboxylic acid, N-methyl morpholine, and O-benzotriazol-1-yl-N,N,N′,N′-teteramethyluronium hexafluorophosphate. The reaction mixture is stirred at ambient temperature for 18 h. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[P:20]([O-:38])([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].O[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([N:47]1[C:51](=[O:52])[C:50]([C:53]2[C:61]3[C:56](=[CH:57][C:58]([N+:62]([O-:64])=[O:63])=[CH:59][CH:60]=3)[N:55]([CH3:65])[CH:54]=2)=[C:49]([C:66]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[N:68]([CH3:75])[CH:67]=2)[C:48]1=[O:76])=[O:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:75][N:68]1[C:69]2[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:66]([C:49]2[C:48](=[O:76])[N:47]([C:45]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][O:21][P:20](=[O:38])([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:46])[C:51](=[O:52])[C:50]=2[C:53]2[C:61]3[C:56](=[CH:57][C:58]([N+:62]([O-:64])=[O:63])=[CH:59][CH:60]=3)[N:55]([CH3:65])[CH:54]=2)=[CH:67]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(C(=O)NCCCCO)C2=O)c2ccccc21
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(C(=O)NCCCCOP(=O)(OCc3ccccc3)OCc3ccccc3)C2=O)c2ccccc21
Temperature: -78 °C
Yield: 82.8 %

Procedure:
Triphenylphosphine (0.86 g, 3.29 mmol) and Dibenzyl phosphate (0.91 g, 3.29 mmol) were added to a solution of 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrole-1-carboxylic acid (4-hydroxybutyl)-amide (prepared as in example 23, 1.41 g, 2.74 mmol) in THF (50 mL). The mixture was cooled to −78° C. Diethyl azodicarboxylate (0.52 mL, 3.29 mmol) was added dropwise over 5 min. The cooling bath was removed and after 2 h, the mixture was evaporated. Chromatography of the residue over silica gel using 2:1 EtOAc/hexane then EtOAc gave phosphoric acid dibenzyl ester 4-{[3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrole-1-carbonyl]-amino}butyl ester (1.76 g, 83%).
Reaction SMILES: [CH2:1]=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[N+:14]([O-:16])=[O:15]>O.CO>[N+:14]([C:13]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:16])=[O:15]
Reactant: O=[N+]([O-])C([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=C(C(=O)OCC)C(=O)OCC
Solvent: CO
Solvent: O
Product: CCOC(=O)C(CC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Freshly distilled diethyl methylene-malonate (8.0 g, 0.046 mol) was added dropwise with stirring over a 10 min period to a solution of 16 g (0.1 mol) of nitroform in 25 ml of water and 40 ml of methanol at 0°-5°. The mixture was stirred 16 hrs at room temperature and was then extracted with 100 ml of methylene chloride. The methylene chloride solution was washed with 10% sodium bicarbonate and with water, dried over sodium sulfate and stripped of solvent under vacuum. Column chromatography on 200 g of silica gel (CCl4 --CH2Cl2), filtration through charcoal and removal of solvent gave 13.0 g (87%) of diethyl 2,2,2-trinitroethylmalonate, mp 24°-25°; NMR (CDCl3), 4.23 (q, 4 H, J=7 Hz, CH2CH3), 3.80 (m, 3 H, CH--CH2) and 1.33 (t, 6 H, J=7 Hz, CH3); IR (neat) 1730 (C=O) and 1600 (NO2) cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)([O-:3])=[O:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>O>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:13][N:12]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridin-2-amine (2.70 g, 11.7 mmol), p-toluenesulfonyl chloride (2.67 g, 14.0 mmol) and pyridine (20 mL) was stirred at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 92%) as a white solid. A mixture of 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 10.7 mmol) thus-obtained, N,N-diisopropylethylamine (2.44 mL, 14.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr, iodoacetamide (2.59 g, 14.0 mmol) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (5.28 g, 99%) as a white solid.
Reaction SMILES: OB1C2C=CC(OC3C=CC(C#N)=C(N4CCOCC4)N=3)=CC=2CO1.[CH2:26]([O:28][C:29]1[N:36]=[C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([B:44]3[O:48][C:47](C)(C)C(C)(C)[O:45]3)=[C:40](C=O)[CH:39]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:27].[BH4-].[Na+]>>[CH2:26]([O:28][C:29]1[N:36]=[C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]3[B:44]([OH:45])[O:48][CH2:47][C:42]=3[CH:43]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32])[CH3:27]
Reactant: CCOc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ccc1C#N
Agent: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1N1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Product: CCOc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Reaction time: 8 h

Procedure:
Experimental procedure for synthesis of 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-2-morpholin-4-yl-nicotinonitrile (D107) is the same as that described in synthesis of (D46). The reaction of 2-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (6) (2.71 g, 7.81 mmol) with NaBH4 (886 mg, 23.4 mmol) gave an orange oil containing D107 upon workup. The oil was fractionated by dry-pack column chromatography as follows: the oil was diluted with 30% MeOH/CH2Cl2 (400 mL) followed by the addition of silica gel (80 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (160 g, 230-400 mesh) and eluted with 1:1:100 acetic acid:MeOH:CH2Cl2. The fractions containing D107 were collected and concentrated to give a light yellow coloured oil. The oil was freeze dried by first diluting with methanol (30 mL) followed by the addition of deionised water (400 mL), the resultant white suspension was frozen in a dry-ice acetone bath and placed overnight on freeze-dryer. A white solid of D107 was obtained (1.82 g, with 30 mol % pinacoldiol present as established by H NMR). To increase purity of D107, it was resubjected to column chromatography and freeze-dried following the same conditions as before to give D107 (402 mg, 17% isolated yield) as a white solid. 1H NMR 400 MHz (d6-DMSO) δ9.25 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.20 (dd, J=7.8, 2.0 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.99 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 1.21 (t, J=7.0 Hz, 3H); Mass Spectrum [M+H+]=297; HPLC purity 97.18% (Maxplot), 97.65% (220 nm).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=1[O:40][CH3:41]>C(Cl)Cl>[OH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:37])=[CH:33][C:32]=1[O:40][CH3:41]
Reactant: CN1CCNCC1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
1-Methylpiperazine (0.58 mL, 5.2 mmol), HOBt (0.70 g, 5.2 mmol.) and EDCl (1.0 g, 5.2 mmol) were added to a solution of 4-hydroxy-3-methoxybenzoic acid (0.69 g, 4.0 mmol.) in dry DCM (40 mL). The mixture was stirred at room temperature for 16 h, washed with saturated aqueous sodium bicarbonate (20 mL), brine, dried over sodium sulphate and evaporated to give the title compound (0.96 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[N:20]1([C:25]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15](=[O:17])[N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:25](=[O:26])[N:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:33][CH2:32]3)[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(pyrrolidinocarbonylmethyl)piperazine to give 4-chloro-N-(4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-benzamide, using general procedure A. Off-white solid. MS 476.1 ([M+H]+)
Reaction SMILES: C([C:4]1[S:5][C:6](Cl)=[CH:7][C:8]=1[O:9][CH2:10][C:11]([OH:13])=[O:12])(O)=O.N1C2C(=CC=CC=2)C=CC=1.C(=O)=O.[ClH:28]>[Cu].O>[Cl:28][CH:10]([O:9][C:8]1[CH:7]=[CH:6][S:5][CH:4]=1)[C:11]([OH:13])=[O:12]
Reactant: Cl
Reactant: O=C(O)COc1cc(Cl)sc1C(=O)O
Agent: [Cu]
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=C(O)C(Cl)Oc1ccsc1

Procedure:
A mixture of 1.63 g of the product of Step C, 3.5 ml of quinoline and 0.24 g of Gattermann copper was heated to 200° C. under nitrogen during which 165 ml of carbon dioxide gas evolved for the water and the mixture was then poured into iced water. 5.6 ml of 10N hydrochloric acid were added thereto and the mixture was extracted with ether. The ether phase was dried and evaporated to dryness and the residue was effloresced with petroleum ether (Bp -60°-80° C.) to obtain 1.2 g of 2-chloro-4-thienyloxy-acetic acid melting at 119° C.