Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([NH2:10])=[NH:9])[CH:3]=1.[Cl:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[CH3:21][C:22]1([CH3:30])[CH2:27][C:26](=[O:28])[CH2:25][C:24](=O)[CH2:23]1.C([O-])(=O)C.[Na+].Cl>C(O)C.O.C(OCC)(=O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:10][C:24]3[CH2:23][C:22]([CH3:30])([CH3:21])[CH2:27][C:26](=[O:28])[C:25]=3[CH:14]([C:13]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:12]=3[Cl:11])[N:9]=2)[CH:3]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: N=C(N)c1cccnc1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)NC(c1cccnc1)=NC2c1ccc(F)cc1Cl
Yield: 26 %

Procedure:
3-Pyridinecarboxamidine hydrochloride (Schaefer F. C., Peters G. A., et al. J. Org. Chem.; 1961; 26(2); 412-418.) 2.164 mmol, 2-chloro-4-fluorobenzaldehyde 2.164 mmol, 5,5-dimethyl-1,3-cyclohexanedione 2.164 mmol and sodium acetate 3.2 mmol were reacted in 8 ml of anhydrous ethanol under refluxing for 18 hr, condensed, and ethyl acetate and water and 1N HCl were added to separate the layers. The water layer was adjusted with concentrated NaOH solution until the pH to be basic, then ethyl acetate was added and extracted twice. The organic layers were combined, dried over anhydrous sodium sulfate and separated by column chromatography to obtain a yellow solid of 0.22 g (yield 26%); mp 186-187° C. 1H-NMR (400 MHz, CDCl3) δ 1.15 (3H, s, CH3); 1.16 (3H, s, CH3); 2.31 (2H, s, CH2); 2.53-2.69 (2H, m, CH2); 6.07 (1H, s, CH); 6.94-6.96 (1H, m, ArH); 7.14-7.17 (1H, m, ArH); 7.23-7.26 (1H, m, ArH); 7.34-7.38 (1H, m, ArH) 8.07-8.09 (1H, m, ArH); 8.69-8.71 (1H, m, ArH); 8.89 (1H, m, ArH). MS (EI) 383.1 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=O)[O:8][C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH:29]3[C:33]4[NH:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=5[C:41](=[O:42])[C:32]=4[CH2:31][NH:30]3)=[CH:23][C:22]=2[O:21]1.C(N(CC)CC)C>O1CCCC1.CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH:29]3[C:33]4[NH:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=5[C:41](=[O:42])[C:32]=4[CH2:31][N:30]3[C:9]([C:7]3[O:8][C:4]4[CH:3]=[C:2]([OH:1])[CH:13]=[CH:12][C:5]=4[CH:6]=3)=[O:11])=[CH:23][C:22]=2[O:21]1
Reactant: O=C(O)c1cc2ccc(O)cc2o1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc2ccc(O)cc2o1)N1Cc2c([nH]c3ccccc3c2=O)C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-hydroxy-2-benzofuranoic acid (0.054 g, 0.3 mmol) in tetrahydrofuran (5 mL) at 0° C. was added dropwise oxalyl chloride (0.046 g, 0.36 mmol) followed by DMF (2 drops). The solution was warmed to 25° C. and stirred for 30 min, then concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), and added to a solution of 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (0.092 g, 0.3 mmol) (prepared as in Example 5) in THF (5 ml), triethylamine (0.045 g, 0.45 mmol) and 4-dimethylaminopyridine (0.01 g, cat.). The solution was stirred for 20 h at 25° C., and then concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography, eluting with 3% methanol in dichloromethane, to yield the product as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH:20][C:27](=[O:30])[CH2:28][CH3:29])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) (150 mg, 0.56 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL), cooled at 0° C., propionyl chloride (57 mg, 0.62 mmol) was added dropwise. Upon complete addition, the ice bath was removed and the reaction continued at room temperature overnight. Then CH2Cl2 (10 mL) and aqueous NaOH 10% (10 mL) were added, the organic layer was separated, and washed with H2O and saturated NaCl. The combined organic layers were dried over Na2SO4, filtered and concentrated in vaccuo. The crude product was purified by column chromatography on silica gel, eluting with an EtOAc/hexane gradient (80-100%), yielding the target product (100 mg, 55%)
Reaction SMILES: C(ON=O)(C)(C)C.[I:8]I.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][C:20](N)=[N:21][CH:22]=2)=[CH:13][CH:12]=1.O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[N:21][C:20]([I:8])=[CH:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: II
Reactant: Nc1cnc(-c2ccc(Cl)cc2)cn1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc(-c2cnc(I)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flask protected from light, 4.90 mL (40.0 mmol) of tert-butylnitrite and 7.61 g (30.0 mmol) of iodine were added to a solution of 4.80 g (23.5 mmol) of 5-(4-chlorophenyl)pyrazin-2-ylamine in 100 mL of carbon tetrachloride and 50 mL of DCM. The mixture was stirred overnight at RT and then combined with 100 mL of water. The organic phase was washed twice with 50 mL of 10% aqueous sodium thiosulfate solution and 50 mL of water, dried over magnesium sulfate, filtered through activated charcoal, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, PE→PE/EtOAc 8:2). Yield: 3.40 g (46% of theoretical); C10H6ClIN2 (M=316.525); calc.: molpeak (M+H)+:317/319 (Cl); found: molpeak (M+H)+:317/319 (Cl); Rf value: 0.55 (silica gel, PE/EtOAc 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:18]2[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:17]2=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:18]2[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:17]2=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OC[C@H]1CCCN21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCCN21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl (R)-7-amino-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 6, 0.525 g) in pyridine (10 mL) and DCM (10 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 0.5M hydrochloric acid solution. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give a pale yellow solid which was triturated with ether and cyclohexane (1:2) to give methyl (R)-7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.820 g).
Reaction SMILES: Cl[CH:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].Cl.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[CH2:38][NH:37][CH2:36][CH2:35]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:28][N:37]2[CH2:36][CH2:35][C:34]3[C:39](=[CH:40][C:41]([O:42][CH3:43])=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:38]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1ccc(C(C#N)(CCCCC(C)Cl)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(C(C#N)(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1OC
Yield: 51.6 %

Procedure:
The procedure of Example 3 is repeated using 4.3 g of α-(5-chlorohexyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 4.25 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This affords 3.05 g of the desired product as a golden gum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:14][CH:15]2[CH2:18][C:17](=[O:19])[CH2:16]2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1SC.[S:20]([O-:25])(O[O-])(=O)=[O:21].[K+].[K+].[Mn]([O-])(=O)(=O)=O.[K+].[CH3:34]C(C)=O>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:14][CH:15]2[CH2:16][C:17](=[O:19])[CH2:18]2)[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:20]([CH3:34])(=[O:25])=[O:21]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CSc1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CC(=O)C2)C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To the solution of 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (0.56 g, 1.88 mmol) dissolved in acetone (15 ml) and cooled to 0° C. in an ice bath was added potassium peroxymonosulfate (Oxone R, 2.3 g, 3.76 mmol) in water (6 ml). The ice bath was removed and the reaction stirred at 25° C. for 20 min. After such a time, it was filtered and washed with acetone and then concentrated in vacuo to remove acetone. The residue was dissolved in ethyl acetate, washed with water and then saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting reaction was dissolved in methanol and cooled to 0° C. in an ice bath. To this was slowly added potassium permanganate (0.32 g, 2.02 mmol) dissolved in water (8 ml). The reaction was then allowed to warm to 25° C. and stirred for 3 h. After this time it was filtered through short celite pad, washed with methanol and evaporated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 3% methanol/methylene chloride+1% acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclobutyl)-propionic acid (0.13 g, 21%) as a white foam: 1H NMR (300 MHz, CDCl3) δ ppm 2.07-2.18 (m, 1H, CH of CH2), 2.26-2.50 (m, 2H, CH and CH of CH2), 2.64-2.85 (m, 2H, 2×CH or 2×CH2), 3.09-3.24 (m, 2H, 2×CH or 2×CH2), 3.28 (s, 3H, SO2CH3), 3.65 (t, J=7.4 Hz, 1H, ArCHCO2), 7.44 (dd, Jm=1.6 Hz, Jo=8.2 Hz, 1H, Ar), 7.55 (d, Jm=1.6 Hz, 1H, Ar), 8.15 (d, Jo=8.2 Hz, 1 H, Ar).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH:12]([CH2:13][CH2:14]Cl)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>C(O)CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH:12]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][N:26]([C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=4)[CH2:31][CH2:30]3)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1cc2c(cc1OC)C(CCCl)OCCC2
Solvent: OCCO
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(CCN1CCN(c3cccc(Cl)c3)CC1)OCCC2
Yield: 34.2 %

Procedure:
A mixture of 2.00 g (7.39 mmol) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl chloride and 2.8 g (14.5 mmol) of 1-(3-chlorophenyl)piperazine is stirred at 85° for 36 hours in 1 ml of ethylene glycol and 10 ml of toluene. Excess toluene is added and the solids are removed by filtration from the warm solution. The organic phase is concentrated. The product was recrystallized from CH2Cl2 and toluene to give 1.09 g of product, m.p. 125°-126°.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13][N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=12>>[CH3:1][O:2][C:5]1[N:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:13][N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: Clc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Reactant: C[O-]
Agent: [Na+]
Product: COc1nnccc1-c1c(-c2ccccc2)nn2ccccc12

Procedure:
To a 28% methanolic solution of sodium methoxide (3 ml) was added 3-(3-chloropyridazin-4-yl)-2-phenylpyrazolo[1.5-a]pyridine (0.61 g). The mixture was refluxed for an hour and evaporated in vacuo. The residue was dissolved in chloroform (20 ml). The chloroform solution was washed with water (5 ml) and a saturated aqueous solution of sodium chloride (5 ml) and dried over magnesium sulfate. The solvent was removed and chromatographed on silica gel (10 g) with n-hexane-ethyl acetate as an eluent. The fractions containing the object compound were combined, evaporated in vacuo, and then recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(3-methoxypyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.30 g).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:14][O:15][C:16](=[O:37])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:28]=2)[CH:19]=1.C(N(CC)C(C)C)(C)C>ClCCCl.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:37])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([S:10]([C:6]2[C:3]3=[N:4][O:5][N:1]=[C:2]3[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:28]=2)[CH:19]=1
Reactant: CCCCc1ccc(CNCc2cccc(CC(=O)OC)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ccc(CN(Cc2cccc(CC(=O)OC)c2)S(=O)(=O)c2cccc3nonc23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Benzofurazan-4-sulfonyl chloride (109 mg, 0.50 mmol) was added to a solution of {3-[(4-butyl-benzylamino)-methyl]-phenyl}-acetic acid methyl ester (163 mg, 0.50 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) in 1,2-dichloroethane. The reaction mixture was stirred at room temperature for 20 h. The reaction was diluted with EtOAc and the organic solution was washed with water followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated to afford (3-{[(benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]-methyl}-phenyl)-acetic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.88 (d, 1H), 7.37–7.41 (m, 1H), 7.06–7.10 (m, 2H), 6.90–6.97 (m, 6H), 4.56 (s, 2H), 4.51 (s, 2H), 3.66 (s, 3H), 3.45 (s, 2H), 2.48 (t, 2H), 1.45–1.53 (m, 2H), 1.23–1.32 (m, 2H), 0.89 (t, 3H); MS 508 (M+18).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1>>[CH3:18][C:14]1[N:13]=[C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Cc1cccc(Cl)n1
Product: Cc1cccc(Oc2ccc(CCO)cc2)n1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 4-(2-hydroxyethyl)phenol and 2-chloro-6-methylpyridine. LC-MS (ESI): m/z 230 [M+H]+; 3.08 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 21.6 %

Procedure:
Prepared from (3-amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G49) (160 mg, 0.5 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (115 mg, 0.5 mmol) according to the general procedure K. Obtained as a white solid (53 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[OH:1][CH:2]([CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]=1)[CH2:3][NH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)COCc1cccc(CN2CCCCC2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(O)COCc1cccc(CN2CCCCC2)c1
Yield: 75.9 %

Procedure:
8.60 g (0.021 mol) of 2-[2-hydroxy-3-[3-(1-piperidylmethyl)benzyloxy]propyl]-1H-isoindole-1,3-dione and 3.3 ml of hydrazine hydrate (80%) are boiled in 80 ml of ethanol for 3 hours. The residue left after concentration of the mixture by evaporation is taken up in 50 ml of water; 8 ml of conc. hydrochloric acid are added and the reaction mixture is filtered. The filtrate is adjusted to pH 12 with conc. sodium hydroxide solution and extracted with 3×40 ml methylene chloride. The organic phase is dehydrated with Na2SO4 and concentrated by evaporation under vacuum. The residue is distilled in a high vacuum. 4.44 g (76%) of a colourless oil, boiling point 145°-155° C./1×10-2 mbar, are obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[O:9]1[CH:15]2[CH:10]1[C:11]([CH3:22])([CH3:21])[O:12][C:13]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=12.O>CS(C)=O.C(OCC)(=O)C>[CH3:21][C:11]1([CH3:22])[C@@H:10]([OH:9])[C@H:15]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[C:14]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:13]=2[O:12]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc2c(c1)C1OC1C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Reaction time: 1 h

Procedure:
2-Pyrrolidone (1.02 g) was added to a suspension of sodium hydride (0.3 g, 80% dispersion in oil) in dry dimethyl sulphoxide (20 ml) under nitrogen at room temperature, and the mixture stirred for 1 h. A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran in dry dimethyl sulphoxide (10 ml) was then added, and the reaction mixture stirred for an additional 16 h. Cautious addition of water and extraction via ethyl acetate gave a crude product (1.84 g) which was chromatographed on silica gel and eluted with 60°-80° C. petroleum ether-ethyl acetate mixtures to give a foam (0.7 g) which was recrystallised from 60°-80° C. petroleum ether-ethyl acetate (0.53 g). Two further recrystallizations from ethyl acetate-pentane gave the analytical sample of the title compound mp 187°-188° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]2[CH:37]=[C:36]3[C:32]([CH2:33][C:34](=[O:38])[NH:35]3)=[CH:31][CH:30]=2)[CH:26]=[CH:27][CH:28]=1>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:33]1[C:32]2[C:36](=[CH:37][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)=[CH:30][CH:31]=2)[NH:35][C:34]1=[O:38])([OH:16])=[O:15]
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-methoxy-phenyl)-2-oxindole (287 mg), and piperidine (2 drops) in ethanol (5 mL) were stirred at 90° C. overnight. The precipitate was filtered and washed with ethanol. The yellow orange solid and potassium hydroxide (4 pellets) were stirred in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 413 mg of 4-(2-Carboxyethyl)-5-[6-(3-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:2]1.F[P-](F)(F)(F)(F)F.[Br:34][C:35]1[S:36][C:37]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:38]([C:40]([OH:42])=O)[N:39]=1.[NH2:51][C:52]1[CH:53]=[N:54][N:55]([CH3:72])[C:56]=1[N:57]1[CH2:62][CH2:61][CH:60]([CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])(C)C)[CH2:59][CH2:58]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:67]([O:66][C:65]([NH:64][CH2:63][CH:60]1[CH2:59][CH2:58][N:57]([C:56]2[N:55]([CH3:72])[N:54]=[CH:53][C:52]=2[NH:51][C:40]([C:38]2[N:39]=[C:35]([Br:34])[S:36][C:37]=2[NH:43][C:44](=[O:45])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:42])[CH2:62][CH2:61]1)=[O:71])[CH2:70][CH2:1][CH3:2]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cn1ncc(N)c1N1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A solution of PyBOP (2.84 g, 5.46 mmol) and 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.39 g, 4.29 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. A solution of tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate (1.2 g, 3.90 mmol) and DIPEA (1.1 mL, 6.24 mmol) in DCM (20 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to yield tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate as a pink solid (2.32 g, 96%). 1H NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 9.64 (s, 1H), 7.23 (s, 1H), 6.86 (t, J=5.8 Hz, 1H), 3.62 (s, 3H), 3.07 (d, J=11.4 Hz, 2H), 2.95 (t, J=11.5 Hz, 2H), 2.87 (t, J=6.3 Hz, 2H), 1.67 (d, J=12.3 Hz, 2H), 1.52 (s, 9H), 1.45 (s, 1H), 1.40 (s, 9H), 1.27-1.16 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+]>C(#N)C>[F:16][CH:12]([F:17])[O:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC(F)F)nc1
Yield: 6.7 %

Procedure:
To a solution of 2-hydroxy-5-nitro pyridine (10 g, 0.071 mol) in acetonitrile (100 mL) was added sodium chlorodifluoroacetate (11.5 g, 0.075 mol). The reaction mass was refluxed for 72 h. The excess of solvent was removed under vacuum and the reaction mass was diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on neutral alumina eluting with 10% EtOAc: Pet.ether to afford 0.900 g of the desired product. 1HNMR (DMSO-d6): δ 7.05 (d, J=8.7 Hz, 1H), 7.53 (d, J=71.4 Hz, 1H), 8.54 (dd, J=8.1 Hz & 5.4 Hz, 1H), 7.91 (s, 1H); MS [M]−: 190.83.