Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C#N

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J32) (318 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (470 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(CC=Cc1cccnc1)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 34 mg of 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-2-propenyl]octanoic acid in 2 mL of ethanol is added 5 mg of 10% palladium on carbon. The mixture is hydrogenated at 1 atmosphere pressure of hydrogen at room temperature for 48 hours. Then the mixture is filtered, washed and evaporated to give an oil which is purified by preparative thin layer chromatography using petroleum ether, ethyl acetate, acetic acid (80:18:2) as solvent to yield 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoic acid of Example 5a.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:37])[C@@H:7]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:19]=12)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)[CH3:2].C1CCN2C(=NCCC2)CC1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:10][C:8]([CH3:9])([CH3:11])[C@H:7]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:20][C:19]=12)=[O:14])[C:6]1[O:37][C:1]([CH3:2])=[N:4][N:5]=1
Reactant: CC(=O)NNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nnc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CC3)C(C)(C)C)o1
Temperature: 150 °C
Yield: 0.1 %

Procedure:
The intermediate 14D (48 mg, 94 mmol) was taken up in THF (1 mL) and added to a 2 mL microwave reaction vial. DBU (21 μL, 0.14 mmol) was added to the reaction, followed by the Burgess reagent (112 mg, 468 mmol). The vial was capped and the reaction mixture was heated to 150° C. for 5 minutes, after which some starting material still remained. Additional Burgess reagent (1 equiv) was added and the reaction was heated to 150° C. for 10 minutes. LC/MS showed that the starting material was consumed. The reaction was diluted with of saturated aqueous NaHCO3 (1 mL) and EtOAc (2 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (2 mL). The organic layers were combined, dried with anhydrous Na2SO4, filtered and evaporated. The residue was purified by Flash chromatography on silica using a gradient from 10% EtOAc/Hexanes to 60% EtOAc/Hexanes. This provided intermediate 14E as a clear oil (25 mg, 54% yield). LCMS (+ESI) m/z 495.3 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]([NH:18][CH3:19])[C:16]#[N:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C1COCC1.O>[Si:1]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]([C:16]#[N:17])[N:18]([CH3:19])[C:27](=[O:28])[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CNC(C#N)C1CCC(CO[Si](C)(C)C(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C(C#N)C1CCC(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To 2-(3-((tert-butyldimethylsilyloxy)methyl)cyclopentyl)-2-(methylamino)acetonitrile (6.0 g, 21.24 mmol) in THF (33 mL), H2O (15 mL) was added, at 0, ° C. Na2CO3 (4.50 g, 42.48 mmol) followed by the dropwise addition of benzyl chloroformate (3.89 mL, 27.6 mmol) over 10 min. The reaction mixture was stirred at 0° C. for 30 min. then at 23° C. for 18 hours. H2O (150 mL) was then added and the organic material was extracted with ethyl acetate (3×100 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The crude material was purified on a Silica gel column (Biotage flash chromatography system), eluted with a gradient of ethyl acetate:hexane (1:4) to (1:1) to afford 3.90 g (44% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.45 (5 H, m), 5.33 (2 H, s), 5.18-5.25 (1H, m), 3.48-3.59 (2 H, m), 3.00 (3 H, s), 2.35-2.47 (2 H, m), 1.55-2.25 (6 H, m), 0.94 (9 H, s), 0.05 (6 H, s). LCMS (+ESI, M+H+) m/z 417.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[CH:12][CH:11]=[CH:10]4)[CH:7]=[CH:6][C:5]=2[CH:4]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:4]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17](=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][CH:12]=[CH:13]4)[C:18]=2[CH:19]=[CH:20][C:3]=1[CH:2]=[O:1]
Reactant: OCc1ccc2c(ccc3c4ccccc4ccc23)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1ccc2c(ccc3c4ccccc4ccc23)c1
Yield: 87.9 %

Procedure:
2-Hydroxymethylchrysene (20C, 8.0 g, 0.031 mol) in CH2Cl2 (2.5 L) was treated with BaMnO4 (Aldrich, 15.9 g, 0.062 mol) and refluxed for 12 h. The reaction mixture was filtered, and concentrated to give a solid, which was then passed through a plug of SiO2 (500 g) using PhCH3 as the eluting solvent. The appropriate fractions were combined and the volume reduced to 75 mL to afford 6.98 g (88%) of chrysene-2-carbaldehyde mp 215°-216.5°, (C, H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:44])[CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O:47][C:48]([CH3:50])=[CH2:49]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([OH:44])[CH2:49][C:48](=[O:47])[CH3:50])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCC(=O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: C=C(C)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)CC(O)(CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.17 h
Yield: 10.3 %

Procedure:
A solution of 50 (160 mg, 0.257 mmol) in anhydrous CH2Cl2 (0.3 mL) was cooled in an ice bath under argon for 10 min. TiCl4 (25 μL) was added, and the resulting mixture was stirred for 10 min. 2-(Trimethylsilyloxy)prop-1-ene (33.4 mg, 0.257 mmol, 0.43 μL) was added. Stirring was continued for 20 min. The reaction mixture was diluted with ice-cold water. CH2Cl2 was added, and the phases were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4). Concentration of the sample under reduced pressure yielded a pale yellow oil, which was purified by column chromatography [silica, hexanes/ethyl acetate (10:1→3:1)] affording a colorless oil (18 mg, 10%): 1H NMR δ 1.04 (s, 18H), 1.85-1.89 (m, 4H), 2.18 (s, 3H), 2.61 (s, 2H), 3.65 (m, 4H), 7.37-6.42 (m, 12H), 7.65-7.67 (m, 8H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19].[NH4+].[OH-]>CCCCCC.CCOCC>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[OH:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1ccc(C=O)cc1OC
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc(C(O)c2ccccn2)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 187.5 ml of 1.6 M solution of butyllithium in hexane was cooled to -40° under nitrogen and 39.5 g (0.25 M) of 2-bromopyridine in 100 ml of ether added dropwise. The mixture was stirred 15 minutes at -40° and a solution of 41.5 g (0.25 M) of 3,4-dimethoxybenzaldehyde in 200 ml of ether added. After stirring at -15° for 45 minutes, the mixture was poured into 500 g ice/100 ml conc. HCl. The separated aqueous layer was made alkaline with conc. NH4OH, extracted with methylene chloride and the dried extract concentrated. The residual oil crystallized from benzene/hexane to give 3,4-dimethoxyphenyl-2-pyridyl carbinol, mp 92°-94°.
Reaction SMILES: [CH2:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:20]1([CH3:27])[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.[CH2:28]1OCOC[O:29]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:20]1([CH3:27])[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[CH:28]=[O:29]
Reactant: Cc1cccc(C)c1
Reactant: C1OCOCO1
Agent: CCCCCCCCCc1ccc(O)c(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: Cc1cccc(C)c1C=O

Procedure:
To a mixture of 26.4 parts of 5-nonylsalicylic acid, 5.9 parts of m-xylene, 3.4 parts of sym-trioxane and 15 parts of acetic acid was added 4.0 parts of p-toluenesulfonic acid (catalyst). After being heated under reflux for 5 hours, the reaction mixture was washed with water, and unreacted m-xylene and water were removed by vacuum distillation to give 38 parts of 5-nonylsalicylic acid-m-xylene-formaldehyde co-condensation product. To 10 parts of the co-condensation product was added gradually a mixture of 0.9 parts of zinc oxide and 0.5 parts of ammonium hydrogencarbonate at a temperature of 150° C. After the completion of the addition, the reaction was allowed to proceed for an additional hour at 150° C. to give 10.8 parts of zinc salt of 5-nonylsalicylic acid-m-xylene-formaldehyde co-condensation product.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([C:7](OCC)=[O:8])[CH2:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1.[NH3:19]>CO>[OH:1][CH:2]1[CH:6]([C:7]([NH2:19])=[O:8])[CH2:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:3]1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1O
Reactant: N
Solvent: CO
Product: NC(=O)C1CN(Cc2ccccc2)CC1O
Yield: 22.1 %

Procedure:
A solution of 11.0 g (44.0 mmol) of 3-hydroxy-4-ethyloxycarbonyl-1-phenylmethyl pyrrolidine (prepared according to E. JAEGER and J. H. BIEL in J. Org. Chem. 1965, 30, (740) in 40 g of 25% ammonia in methanol was heated at 100° C. under pressure overnight. The solution was cooled and evaporated to dryness. The oily residue was purified by chromatography using dichloromethane-methanol (85:15) to yield 2.14 g (22%) of the title compound. M.P. 128° C.
Reaction SMILES: [OH:1][C@:2]1([CH3:35])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:23])[CH3:22])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:34])([F:33])[F:32])=[N:27][NH:28][C:29]=2[CH3:30])=[O:8])[CH2:3]1.Cl.C[C@]1(O)CONC1.[N+](C1C=C(S(OC[C@@]2(C)CO2)(=O)=O)C=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[OH:1][C@@:2]1([CH3:35])[CH2:6][O:5][N:4]([C:7]([C:9]2[C:17]3[C:16](=[O:18])[N:15]([CH3:19])[C:14](=[O:20])[N:13]([CH:21]([CH3:22])[CH3:23])[C:12]=3[S:11][C:10]=2[CH2:24][C:25]2[C:26]([C:31]([F:32])([F:33])[F:34])=[N:27][NH:28][C:29]=2[CH3:30])=[O:8])[CH2:3]1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cc1sc2c(c1C(=O)N1C[C@](C)(O)CO1)c(=O)n(C)c(=O)n2C(C)C
Agent: C[C@@]1(O)CNOC1
Agent: C[C@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1[nH]nc(C(F)(F)F)c1Cc1sc2c(c1C(=O)N1C[C@@](C)(O)CO1)c(=O)n(C)c(=O)n2C(C)C
Reaction time: 3 h

Procedure:
To a suspension of the product of example 10 part a) (0.130 mg) and (4R)-4-methyl-4-isoxazolidinol hydrochloride (42 mg, prepared by the method of example 1 steps a) to d) using [(2R)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate) in anhydrous THF (6 ml), was added triethylamine (120 mg) and the mixture was cooled in an icebath. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetamethyluronium hexafluorophosphate (120 mg) was added and the mixture was allowed to warm to, whereupon it was stirred for 3 hr. All volatiles were removed in vacuo and the residue was chromatographed (SiO2/1:1 CH2Cl2-EtOAc) to effect primary purification. Further purification by RPHPLC afforded the title compound as a solid (35 mg).
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=4)[N:22]=3)[CH2:17][CH2:16]2)=[CH:9][N:8]=1)=[O:6]>CO.O>[NH2:13][C:12]1[C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=[C:10]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:30]=[C:29]([NH2:31])[C:28]4[C:23](=[CH:24][C:25]([O:34][CH3:35])=[C:26]([O:32][CH3:33])[CH:27]=4)[N:22]=3)[CH2:17][CH2:16]2)[N:11]=1
Reactant: COC(=O)c1ncc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2nc(N3CCC(Nc4cnc(C(=O)O)c(N)n4)CC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 101.4 %

Procedure:
Potassium hydroxide (0.53 g, 9.46 mmol) was added to a solution of (2) (0.23 g, 0.47 mmol) in MeOH/H2O (20 mL, 10%; v/v) at 25° C. The reaction mixture was heated at 85° C. for 12 h then cooled to room temperature. The mixture was concentrated, acidified with HCl (aq) (20 mL, 3M) and the desired product was filtered and rinsed with cold H2O to give 0.21 g (93%) of the title compound: 1H NMR (DMSO) δ 12.45 (br s, 1H), 8.78 (br, 2H), 8.37 (s, 1H), 7.78 (s, 1H), 7.68 (s, 1H), 7.38 (s, 1H), 5.19 (br s, 3H), 4.56 (m, 2H), 4.13 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.41 (m, 2H), 2.04 (m, 2H), 1.54 (m, 2H); 13C NMR (DMSO) δ 167.0, 161.3, 155.8, 155.1, 154.4, 151.0, 146.7, 136.3, 121.3, 121.0, 105.2, 101.6, 99.3, 56.3, 56.0, 46.5, 43.3, 30.5; HRMS (FAB) m/z 441.1988 (M+H)+ (C20H24N8O4 requires 441.1999).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[C:6]([NH:11]C(=O)C)[C:5]=1[N+:15]([O-:17])=[O:16].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1c(Br)ccc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of 3-acetylamino-6-bromo-2-nitro-benzoic acid methyl ester (iii, 5.53 g, 17.42 mmol) and BF3.Et2O (10.0 mL, 78.91 mmol) in MeOH (100 mL) was heated to reflux for 2 h and cooled to room temperature. The reaction mixture was neutralized with solid NaHCO3 and the solvent was removed under reduced pressure. The solid residu was dissolved in EtOAc (400 mL) and washed with H2O (3×200 mL), brine (1×200 mL), and dried with Na2SO4. The solvent was removed under reduced pressure to yield the desired product iv as an orange solid (4.74 g, 100%). 1H NMR (CDCl3): δ 7.40 (d, J=9.3 Hz, 1H), 6.70 (d, J=9.3 Hz, 1H), 6.09 (br s, 2H), 3.90 (s, 3H). Anal. Calcd for C8H7BrN2O4: C, 34.93; H, 2.57; N, 10.18. Found: C, 35.08; H, 2.49; N, 10.06.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[NH:12][C:11]([C:13](=[O:24])[NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[N:10][C:9]=12)=[O:4].Br[CH2:26][C:27]1[CH:31]=[C:30]([C:32]2[S:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[O:29][N:28]=1.CC#N.O>C(O)=O>[Cl:37][C:34]1[S:33][C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:12]3[C:8]4=[CH:7][S:6][C:5]([C:3]([OH:2])=[O:4])=[C:9]4[N:10]=[C:11]3[C:13](=[O:24])[NH:14][CH:15]3[CH2:16][CH2:17][N:18]([CH:21]4[CH2:23][CH2:22]4)[CH2:19][CH2:20]3)[CH:31]=2)=[CH:36][CH:35]=1.[Cl:37][C:34]1[S:33][C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:10]3[C:9]4=[C:5]([C:3]([OH:2])=[O:4])[S:6][CH:7]=[C:8]4[N:12]=[C:11]3[C:13](=[O:24])[NH:14][CH:15]3[CH2:16][CH2:17][N:18]([CH:21]4[CH2:23][CH2:22]4)[CH2:19][CH2:20]3)[CH:31]=2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1scc2[nH]c(C(=O)NC3CCN(C4CC4)CC3)nc12
Solvent: CC#N
Solvent: O
Solvent: O=CO
Product: O=C(O)c1scc2c1nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Product: O=C(O)c1scc2nc(C(=O)NC3CCN(C4CC4)CC3)n(Cc3cc(-c4ccc(Cl)s4)on3)c12

Procedure:
3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid and 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-4-carboxylic acid were prepared by a procedure according to example 81 starting from 236.0 mg (0.68 mmol) 2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-3H-thieno[3,4-d]imidazole-6-carboxylic acid methyl ester and 188.7 mg (0.68 mmol) 3-bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole. Hydrolysis of the resulting esters and purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave the title compounds as their formiates in form of white amorphous solids. Structural assignment of both isomers was achieved by NOE-spectroscopy.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1.[CH3:17][C:18]1[C:26]2[CH2:25][O:24][C:23](=[O:27])[C:22]=2[CH:21]=[CH:20][C:19]=1[C@H:28]1[CH2:30][O:29]1.CCN(C(C)C)C(C)C>C(O)C>[OH:29][C@H:28]([C:19]1[C:18]([CH3:17])=[C:26]2[C:22](=[CH:21][CH:20]=1)[C:23](=[O:27])[O:24][CH2:25]2)[CH2:30][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:4][CH2:3]1
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCC3(CC2)C(=O)Nc2ccccc23)ccc2c1COC2=O
Temperature: 80 °C

Procedure:
Commercially available spiro[indoline-3,4′-piperidin]-2-one hydrochloride (500 mg, 2.10 mmol) was combined with 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (I-4A) (398 mg, 2.10 mmol) and DIEA (439 μL, 2.51 mmol) in ethanol (7 mL) and heated at 80° C. for 3 h. The reaction mixture was concentrated and purified by MPLC eluting first with 30% ethyl acetate/hexanes and then with 10% methanol/DCM to afford the title compound which was a mixture of regioisomers. MS-ESI (m/z): 393 (M+1)+;
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:26][C:27]1[S:28][C:29]([CH:32]2[CH2:34][CH2:33]2)=[N:30][N:31]=1>C(#N)C>[CH:32]1([C:29]2[S:28][C:27]([CH2:26][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])=[N:31][N:30]=2)[CH2:34][CH2:33]1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCc1nnc(C2CC2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(C2CC2)s1
Yield: 61 %

Procedure:
To a solution of 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 153A) (0.200 g, 0.793 mmol) in anhydrous acetonitrile (30 mL) was added Cs2CO3 (0.298 g, 0.915 mmol) and 2-(bromomethyl)-5-cyclopropyl-1,3,4-thiadiazole (0.300 g, 1.37 mmol). The mixture was heated under N2, for 2 h. Upon cooling, the mixture was partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford a pure product (0.189 g, 61% yield): MS (ES) m/z 390 (M+).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[O:8][CH:9]=1)([OH:4])(=[O:3])=[O:2].S(Cl)([Cl:15])=O>>[S:1]([C:5]1[CH:6]=[C:7]([C:10]([Cl:15])=[O:12])[O:8][CH:9]=1)([OH:4])(=[O:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(S(=O)(=O)O)co1
Product: O=C(Cl)c1cc(S(=O)(=O)O)co1

Procedure:
4-Sulfo-2-furoic acid (0.1 mole) is stirred with 30 ml of thionyl chloride (SOCl2) for 40 minutes at 60° C. The reaction mixture is evaporated to dryness to give 4-sulfo-2-furoyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]#[C:20][Si](C)(C)C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:25]#[N:26])[CH:5]=[CH:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([C:19]#[CH:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:25]#[N:26])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To 800 mg of 4-(3-bromo-phenylamino)-6-trimethylsilanylethynyl-[1,7]naphthyridine-3-carbonitrile in 20 mL of tetrahydrofuran at 0° C. under an inert atmosphere was added 2.5 mL of 1 M tetrabutylammonium fluoride/tetrahydrofuran. After 1 hour at ambient temperature, the reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried with sodium sulfate and evaporated. The product was purified by flash chromatography on silica gel to give 300 mg of 4-(3-bromo-phenylamino)-6-ethynyl-[1,7]naphthyridine-3-carbonitrile: melting point 224° C. (decomposed); mass spectrum (m/e): M+H 349.1, 351.1.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][C:23]([O:25]C)=[O:24])[CH:20]=3)[N:13]3[CH:32]=[CH:33][N:34]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1>O.CO>[CH3:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])[CH:20]=3)[N:13]3[CH:32]=[CH:33][N:34]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1
Reactant: COC(=O)CC(CC(=O)OC)n1cc(-c2nc(-c3cnn(C)c3)cc3nccn23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC(=O)O)CC(=O)O)c3)n2)cn1
Reaction time: 72 h
Yield: 65.3 %

Procedure:
Lithium hydroxide hydrate (0.0813 g, 1.94 mmol) was dissolved in water (2 mL) and was added to a solution of dimethyl 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedioate (0.205 g, 0.484 mmol) in MeOH (4 mL). After stirring 3 days the reaction was concentrated to remove the MeOH and was then acidified to pH 4 with 1 N HCl (approximately 2 mL). Cooling resulted in a solid which was filtered and washed with MeOH. The filtrate was slightly concentrated to provide a second crop of product which was combined to provide 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedioic acid (125 mg, 65% yield). MS (apci) m/z=396.2 (M+H).