Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[OH:9])=[CH:4][C:3]=1[O:24][CH3:25]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanol (0.58 g, 1.57 mmol) in CH2Cl2 (5 mL) was added activated manganese dioxide (0.80 g, 7.86 mmol). The reaction mixture was stirred overnight at rt. Additional manganese dioxide (0.80 g, 7.86 mmol) was added and the reaction stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 and filtered through celite and the solid was washed with CH2Cl2. The filtrate was concentrated under reduced pressure to yield (4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanone (0.56 g, 98% yield). HPLC: RT=4.048 minutes (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient, flow rate 4 mL/min, monitoring at 220 nm); LCMS: [M+H] 365.2 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous methanol containing 0.1% TFA over a 2 minute gradient, flow rate 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3): 7.5-7.1 (m, 6H), 5.92 (tt, J=2.2, 53.6 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>O1CCCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:15](=[O:16])[NH:14][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(N2CCOCC2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(N3CCOCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
A solution of crude 4-morpholin-4-yl-benzene-1,2-diamine (0.75 g, 3.9 mmol) in tetrahydrofuran (4 mL) was treated dropwise with a solution of carbonyldiimidazole (0.76 g, 4.7 mmol) in tetrahydrofuran (12 mL). The reaction mixture was stirred for 16 h at room temperature, and the solid product was collected by filtration and recrystallized from ethanol to afford the white solid product (0.47 g, 55%). See, J. Am. Chem., Soc., 118:4018 (1996).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[CH2:20]([NH2:22])[CH3:21]>C1COCC1>[CH2:20]([NH:22][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH3:21]
Reactant: CCN
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])c(F)c1
Solvent: C1CCOC1
Product: CCNc1cc(OCCCN(CC)CC)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
A solution of 2-fluoro-4-(3-diethylamino-1-propoxy)nitrobenzene (2 mmol; preparation described in Example 5) in THF (5 mL) is treated with ethylamine (4 mmol) at rt. After completion of the reaction, the reaction mixture is concentrated in vacuo. The residue is redissolved in EtOAc (10 mL), washed with saturated sodium bicarbonate solution, water, and brine. The organic phase is then dried over sodium sulfate and the solvent is removed in vacuo to afford the product, 2-(ethylamino)-4-(3-diethylamino-1-propoxy)nitrobenzene (520 mg) which was used for further transformation without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]2[CH2:11][CH2:10][C@:9]3([OH:26])[C@H:12]4[C@H:22]([CH2:23][CH2:24][C@:7]23[CH3:8])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([OH:25])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)=[CH:2]1.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>O1CCCC1>[CH2:31]([O:25][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@:9]3([OH:26])[CH2:10][CH2:11][C@@H:6]2[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH2:16]1)[CH:30]=[CH2:29]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Reaction time: 20 h
Yield: 87 %

Procedure:
To a solution of 0.60 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377) in 50 ml of dry tetrahydrofuran, 0.44 g of sodium hydride (60% dispersion in mineral oil) were added under nitrogen atmosphere at room temperature and the resulting mixture was stirred at reflux temperature for 6 hrs; 1.4 g of allyl bromide were added and the reflux continued for further 20 hrs. The mixture was quenched with water and the organic solvent was distilled under reduced pressure. The residue was extracted with ethyl acetate, the organic solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 0.58 g of 3β-(prop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[NH:39][C:38]1=[O:46])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][CH2:35][CH2:36][N:37]3[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[NH:39][C:38]3=[O:46])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: O=c1[nH]c2ccccc2n1CCCS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CCCn3c(=O)[nH]c4ccccc43)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrimidin-2-amine and 1-(3-((2-bromophenyl)sulfonyl)propyl)-1H-benzo[d]imidazol-2(3H)-one. MS (ESI): mass calcd. for C26H22FN5O3S, 503.14; m/z found, 503.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.45 (s, 2H), 8.12-8.03 (d, J=7.8, 1H), 7.83-7.75 (m, 1H), 7.75-7.66 (m, 1H), 7.45-7.30 (m, 2H), 7.27-7.19 (d, J=11.5, 1H), 7.09-6.88 (m, 6H), 3.79-3.72 (t, J=6.5, 2H), 2.97-2.88 (dd, J=9.7, 6.3, 2H), 1.79-1.68 (m, 2H).
Reaction SMILES: C(OC[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)C=C.ClC1C=CC(CN2C3C(=[C:33]([CH2:38][OH:39])C=CC=3)C=C2)=CC=1.C(Br)C=C.[H-].[Na+]>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:10]2[C:11]3[C:7](=[C:6]([CH:38]([OH:39])[CH3:33])[CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)=[CH:21][CH:20]=1
Reactant: OCc1cccc2c1ccn2Cc1ccc(Cl)cc1
Reactant: C=CCOCc1cccc2c1ccn2Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: CC(O)c1cccc2c1ccn2Cc1ccc(Cl)cc1

Procedure:
2-[4-[(allyloxy)methyl]-1-(4-chlorobenzyl)-1H-indole, oil (prepared by alkylation of [1-(4-chlorobenzyl)-1H-indol-4-yl]methanol with allyl bromide in DMF in the presence of NaH, at room temperature for 3 h).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:24]([OH:26])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)N=C=NC(C)C.CN(C1C=CC=CN=1)C.CN1C=CN=C1.ClCCl.CN([CH:74]=[O:75])C>ClCCl>[CH3:74][O:75][C:21]1[CH:20]=[CH:19][C:18]([CH:5]2[NH:1][CH:2]([C:24]([OH:26])=[O:25])[CH2:3][S:4]2)=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: CN(C)C=O
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(C2NC(C(=O)O)CS2)cc1
Reaction time: 9 h

Procedure:
Commercially available Fmoc-Cys(Trt) was attached to the linker based solid support 1 by DIC/DMAP procedure. The solid support (1.0 g) having substitution 0.4 meq/g was placed in reaction vessel and allowed to swell in dichloromethane (DCM) under nitrogen stirring. After 30 min. the resin was filtered and washed with DCM. To this resin a solution of Fmoc-Cys(Trt) (0.70 g, 1.2 mmol) dimethylaminopyridine (DMAP) or N-methyl imidazole (NMI) (0.4 mmol) in DCM:DMF (1:1) 20 ml and was added. This mixture was stirred for 8-10 hrs. The resin was washed three times with DCM and dried. An aliquot of this resin was tested to check the loading by the treatment with 20% piperidine and subsequently recording the absorbance in UV [Method A]. It came out to be 90% loading. The resin bearing Fmoc-Cys(Trt) was treated with 20% piperidine in DCM:DMF (1:1) 20 ml for 20 min to remove Fmoc group. The resin was washed three times with DCM and then treated with 10% trifluoric acid (TFA)/Bu3SiH in DCM for 30 min (three times) to remove the trityl group of Cys. After washing the resin with DCM 3 times, a solution of p-anisaldehyde (0.5 ml) in DCM:DMF (1:1) 15 ml was added under stirring and the stirring was continued for 8-10 hrs. The resin was washed three times with DCM and dried. It was treated with a mixture of dioxan-MeOH-4N. NaOH (30:9:1, 20 ml) for 30 min under stirring and the resin was filtered and washed with 2 ml of water. The combined filtrate was evaporated in vacuo. The residue was taken in water and extracted with ether. The aqueous layer acidified with 1N hydrochloric acid and extracted with EtOAc (3×70 ml). The combined EtOAc layer was washed with water and brine then dried over Na2SO4 and evaporated in vacuo to yield 2-(4-methoxyphenyl) thiazolidine-4-carboxylic acid as white crystalline material. Yield: 0.061 g, 72%; m.p. 150-51° C.; FAB-MS [M+H]+ 239; 1H NMR (DMSO-d6) δ: 3.5 (m, 2H), 3.7 (s, 3H), 4.8 (bs, 1H), 5.9 (bs, 1H), 6.8-7.1 (Abq, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9]C(=O)O[C:12](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C=O)C>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[C:12]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:13]
Reactant: Nc1ccc(Br)cc1
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2ccc(Br)cc2)c1N

Procedure:
A solution of 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (1.50 g, 7.70 mmol) and 4-bromoaniline (1.40 g, 8.10 mmol) in anhydrous DMF (10 mL) was stirred at 115° C. for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give 2-amino-N-(4-bromo-phenyl)-3-methoxy-benzamide. Yield: 1.49 g (60%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([N:21]2[C:25]([OH:26])=[CH:24][CH:23]=[N:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH3:27][C:28]1[C:36]([C:37]2[CH2:41][CH2:40][O:39][N:38]=2)=[C:35]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:27][C:28]1[C:36]([C:37]2[CH2:41][CH2:40][O:39][N:38]=2)=[C:35]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=[CH:33][C:29]=1[C:30]([C:24]1[CH:23]=[N:22][N:21]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:25]=1[OH:26])=[O:31]
Reactant: Oc1ccnn1C1CCCC1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1C1=NOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(C(=O)c2cnn(C3CCCC3)c2O)ccc(S(C)(=O)=O)c1C1=NOCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.9 g (9.4 mmol) of dicyclohexylcarbodiimide and 1.3 g (8.8 mmol) of 1-cyclopentyl-5-hydroxy-1H-pyrazole were added to a solution of 2.5 g (8.8 mmol) of 2-methyl-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid in 100 ml of dioxane, and the mixture was stirred at room temperature for 12 hours. Solid components were then filtered off and the filtrate was admixed with 1.5 g (10 mmol) of potassium carbonate and refluxed for 4 hours. The solvent was removed, the residue was then taken up in water and the mixture was washed with ethyl acetate, and then adjusted to pH 3 using 10% strength hydrochloric acid and extracted with methylene chloride. The solvent of the resulting organic phase was distilled off, the residue was taken up in 300 ml of aqueous potassium carbonate solution, insoluble components were filtered off, the pH was adjusted to 3 using 10% strength hydrochloric acid and the resulting precipitate was separated off and dried. Yield: 1.5 g (42% of theory) of 4-[2-methyl-3-(4,5-dihydro-isoxazol-3-yl)-4-methylsulfonylbenzoyl]-1-cyclopentyl-5-hydroxy-1H-pyrazole
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=1.O>CC(N(C)C)=O>[I:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1CCNC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Ic1ccc(N2CCCC2)nc1
Temperature: 120 °C

Procedure:
Pyrrolidine (1.74 ml) was added to 2-chloro-5-iodopyridine (1 g) in dimethylacetamide (5 ml) and the solution heated at 120° C. for 4 h. After cooling, the reaction mixture was poured into water (60 ml) and the solid precipitate collected by filtration. Recrystallisation from ethyl acetate gave the product as off-white needles (0.33 g); the remaining material was adsorbed onto silica and purified by column chromatography eluting with 0 to 3% ethyl acetate in hexane to give a white solid (0.65 g).
Reaction SMILES: O[C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[N:17][OH:18])[C:13]([F:16])([F:15])[F:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O>C1COCC1>[CH2:8]([C:7]1[C:2]2[O:18][N:17]=[C:12]([C:13]([F:14])([F:15])[F:16])[C:3]=2[CH:4]=[CH:5][C:6]=1[OH:11])[CH2:9][CH3:10]
Reactant: CCCc1c(O)ccc(C(=NO)C(F)(F)F)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(2,4-Dihydroxy-3-propylphenyl)-2,2,2-trifluoroethanone oxime (prepared by the method described in WO 97/28137, 4.2 g, 15.96 mmol) and triphenylphosphine (8.82 g, 33.6 mmol) were dissolved in THF (250 mL) and the mixture was cooled to 0° C. A solution of diethyl azodicarboxylate (5.02 mL, 32.0 mmol) in THF (150 mL) was then slowly added over a period of 30 minutes. The reaction mixture was stirred for 1 h at 0° C. After addition of water (500 mL), the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was removed in vacuo and the product purified via silica gel flash chromatography (ethyl acetate/hexane (v/v)=1:6). The product was obtained as a white-yellow powder in a yield of 1.96 g (8.0 mmol, 50%). 1H NMR (300 MHz, CDCl3) δ 1.00 (t, 3H), 1.73 (m, 2H), 2.88 (t, 2H), 5.34 (s, 1H), 6.93 (d, 1H), 7.48 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27](O)=[O:28])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:30])[CH2:9]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.C1N=C[N:37](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([N:22]4[CH2:26][CH2:25][CH2:24][CH:23]4[C:27]([NH2:37])=[O:28])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:30])[CH2:9]2)=[C:4]([C:31]([F:33])([F:32])[F:34])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(=O)O)s1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(N2CCCC2C(N)=O)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
Crude 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxylic acid (570 mg, 1.094 mmol) charged to a reaction flask was dissolved in THF (23 mL). To it was added CDI (649 mg, 4.38 mmol) and the reaction mixture was heated to reflux for 1 hour. After cooling down to room temperature excess NH4OH (28% NH3)(23 ml) was added dropwise via addition funnel. The reaction mixture was left to stir at room temperature for 10 minutes, then it was diluted with ethyl acetate, acidified (pH acidic) using 10% HCl (aqueous) and stirred for 5 minutes. The layers were separated, and the organic layer washed with saturated brine, dried over MgSO4, concentrated. Crude product containing a significant amount of starting acid by TLC was subjected to the same reaction and work up conditions. After reaction completation crude was purified via flash column chromatography to yield 1-(5-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)pyrrolidine-2-carboxamide as white solid (180 mg, 31% yield). HRMS: calcd for C21H24F4N4O3S2+H+, 521.12987. found (ESI-FTMS, [M+H]1+), 521.13026.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:24]=1[NH2:25]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[C:24]([NH:25][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])[CH:26]=1
Reactant: COc1ccc(Cl)cc1N
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COc1ccc(Cl)cc1NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2-methoxy-5-chloroaniline (61 mg, 0.39 mmol). The title compound was obtained as a yellow solid (110 mg, 69% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.17 (1H, s), 9.00 (2H, s), 8.76 (1H, s), 7.57 (1H, m), 7.27 (1H, m), 7.13 (1H, m), 3.83 (3H, s). MS m/z: 488.02, 490.07 [M+H]+.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14](O)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:18]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])=[CH:17][C:13]=1[C:14]([NH:47][CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=1)=[O:15])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)O)c1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(OC/C=C(\C)CCC=C(C)C)c(C(=O)NCCc2ccncc2)c1
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
2,5-digeranyloxybenzoic acid(2.40 g) was dissolved in chloroform(40 ml) and triethylamine(1.58 ml), and then diphenylphosphinic chloride(1.08 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.69 g) added thereto, was stirred for 1 hour at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.90 g of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnccn2)c2c(N)ncnc21
Temperature: 120 °C
Yield: 24.8 %

Procedure:
3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Intermediate D2a, 60 mg, 0.118 mmol), 2-(tributylstannyl)pyrazine (0.072 mL, 0.236 mmol), Pd(PPh3)4, (13.61 mg, 0.012 mmol) and LiCl (4.99 mg, 0.118 mmol) were reacted in dioxane (1.2 mL), purged under argon and heated at 120° C. overnigth. The reaction was quenched by the addition of 1M HClaqueous (2 ml), and the solids collected by filtration. The solid crude was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile (prior to drying 5 mL of 2M HClaqueous was added). The resulting white solid was triturated in Et2O. to give (13.5 mg, 24.8%) the title compound.
Reaction SMILES: [CH2:1]([C:11]1[CH:30]=[CH:29][C:14]([C:15]([NH:17][C:18]2([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][NH:20][CH2:19]2)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:31]=O>>[CH2:1]([C:11]1[CH:30]=[CH:29][C:14]([C:15]([NH:17][C:18]2([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][N:20]([CH3:31])[CH2:19]2)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(C(=O)NC2(CC(=O)OCC)CCNC2)cc1
Reactant: C=O
Product: CCCCCCCCCCc1ccc(C(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Yield: 75 %

Procedure:
According to the method described in example 17c, ethyl 2-(3-(4-decylbenzamido)-pyrrolidin-3-yl)acetate was reacted with formalin to give the title compound as a yellow oil (58 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, 2H, J=7.9 Hz), 7.21 (d, 2H, J=8.1 Hz), 6.70 (s, 1H), 4.10 (q, 2H, J=7.1 Hz), 3.17-2.82 (m, 4H), 2.77-2.67 (m, 2H), 2.63 (t, 2H, J=7.8 Hz), 2.37 (s, 3H), 2.35-2.30 (m, 1H), 1.64-1.55 (m, 2H), 1.36-1.24 (m, 14H), 1.20 (t, 3H, J=7.3 Hz), 0.89 (t, 311, J=6.6 Hz); MS ESI 431.4[M+H]+, calcd for [C26H42N2O3+H] 431.32.