Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCN)=[O:11])[C@H:3]2[NH:19][C:20]([NH:22][C@@H:2]12)=[O:21].CC1(C)C(/C=C/C=C/C=C2\C(C)(C)C3C(N\2CCCCCC(ON2C(=O)CCC2=O)=[O:53])=CC=CC=3)=[N+](C)C2C1=CC=CC=2.C(N(CC)CC)C>CS(C)=O>[OH:53][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:22][C:20]([NH:19]2)=[O:21])[CH2:1][S:5]1)=[O:11]
Reactant: NCCCCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: C[N+]1=C(/C=C/C=C/C=C2/N(CCCCCC(=O)ON3C(=O)CCC3=O)c3ccccc3C2(C)C)C(C)(C)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Biotin Cadaverine (Sigma Aldrich) was conjugated to Cy5 NHS ester (Amersham Biosciences) in DMSO by adding triethylamine for one hour. The conjugate was purified on a Sephadex LH20 column (Amersham Biosciences) by collecting the first ˜500 μl of the coloured fraction. The concentration of the conjugate was determined by preparing a standard curve of Cy5 NHS Ester dye by diluting it in steps of five (resulting in 205, 41.1, 8.21, 1.64, 0.329 and 0 nM). An aliquot of the conjugate was diluted by a factor of 100. Based on the standard curve, we evaluated the concentration to be 11 mM. For biotin assay experiments the biotin conjugate was diluted to 2.2, 1.1, 0.22, 0.044 nM. In an assay experiment, the scanner was operated in line-scanning mode (˜2 sec/line) across the streptavidin line, resulting in data collection also from areas with no biotin. After a few seconds of scanning, 40 μl of biotin solution was dispensed on the chip and data was recorded for about 3.5 minutes. A new chip was used for each experiment.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]2[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:21])C.[OH-].[Na+].[Na]>C(O)C>[Cl:21][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[C:10]=2[CH:19]=[CH:20][C:7]=1[O:6][CH2:5][C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccco3)noc2c1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc2c(-c3ccco3)noc2c1Cl

Procedure:
To a boiling suspension of 15.0 g of ethyl[(7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl)oxy]acetate, Example 7, in 500 ml of boiling 95% ethyl alcohol there is added 10 ml of a 50% sodium hydroxide solution causing the sodium salt to precipitate out almost immediately. An additional 300 ml of 95% ethyl alcohol is added and boiling is maintained for 30 minutes. The reaction mixture is permitted to cool slightly, after which 100 ml of a 5% hydrochloric acid solution is added thereto. The product begins to separate with cooling, 250 ml of water is added and the diluted mixture is chilled with ice. The precipitate is collected by filtration and recrystallized from isopropyl alcohol to yield the product {[7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid having a melting point of 230° to 233° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([C:16]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:20][C:19]3[CH:21]=[CH:22][C:23]([CH2:25][C:26](Cl)=[O:27])=[CH:24][C:18]=3[O:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:29]1([C:16]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:20][C:19]3[CH:21]=[CH:22][C:23]([CH2:25][C:26]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[O:27])=[CH:24][C:18]=3[O:17]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)c1c[nH]c2ccccc12

Procedure:
The title compound was prepared by a similar method to that of Preparation 4 using indole and (2,2-diphenyl-1,3-benzodioxolan-5-yl)acetyl chloride (prepared from the corresponding carboxylic acid [see Preparation 7] by a similar method to that of Preparation 3) as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11](C(OC(C)(C)C)=O)[CH3:12])[CH2:7][CH2:6]1)=[O:4].[ClH:20]>CCOC(C)=O>[ClH:20].[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of trans-4-[(tert-Butoxycarbonyl)(methyl)amino]cyclohexanecarboxylic acid methyl ester (3.69 mmol, 1.0 g) is dissolved in EtOAc (5 mL), cooled to 0° C. and treated with 4M HCl in ethyl acetate (5 mL). The mixture is stirred at room temperature for 5 hours. After the mixture is concentrated under reduced pressure, 100 mL of ethyl ether is added. The solid precipitate is filtrated, washed with ethyl ether and dried under reduced pressure to obtain 700 mg (91%) of trans-4-(methylamino)cyclohexanecarboxylic acid methyl ester hydrochloride as white solid. ESI-MS m/z: 171 [M+1]+, Retention time 1.00 min (condition B).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[C:15]([F:21])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:8][C:6]2[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([OH:1])[CH:7]=2)=[C:15]([F:21])[CH:14]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccc(Br)cc2F)cc1O
Yield: 75.4 %

Procedure:
1-(2,4-dihydroxyphenyl)ethanone (25.3 g, 0.17 mol) and 4-bromo-1-bromomethyl-2-fluorobenzene (44.6 g, 0.17 mol) were dissolved in DMF (150 mL). Potassium carbonate (11.8 g, 0.09 mol) was added to the solution under ice-cooled conditions, and the mixture was stirred under ice-cooled conditions and further stirred at room temperature for 12 hours. Again, potassium carbonate (11.8 g, 0.09 mol) was added to the mixture under ice-cooled conditions, and the mixture was stirred under ice-cooled conditions for 30 minutes and further stirred at room temperature for 12 hours. Methanol (100 mL) was added to this reaction solution, and the mixture was stirred at 80° C. for 1 hour. Thereafter, water (150 mL) was added to the mixture, and precipitated crystals were filtered and washed with methanol. The crystals were vacuum-dried at 60° C. for 2 hours, yielding 1-[4-(4-bromo-2-fluorobenzyloxy)-2-hydroxyphenyl]ethanone (43.5 g, yield: 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][CH3:15])=[C:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25](C)([CH3:27])[CH3:26])=[O:23])[CH2:20][CH:21]=2)[N:10]=[N:9]1>Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][CH3:15])=[C:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:20][CH:21]=2)[N:10]=[N:9]1
Reactant: COCc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1F
Agent: Cl
Product: COCc1c(C2=CCN(C(=O)OC(C)C)CC2)nnn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
tert-Butyl 4-[1-(2-fluorophenyl)-5-methoxymethyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (5.4 mg) prepared in the above 4) was dissolved in 2.0 ml of a 10% methanolic solution of hydrochloric acid followed by stirring at room temperature for 30 minutes. The solvent was evaporated in vacuo followed, without purification, by dissolving in 0.5 ml of pyridine and 0.02 ml of isopropyl chloroformate was added to the solution followed by stirring for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the mixture was extracted with ethyl acetate, the extract was dried over sodium sulfate and the solvent was evaporated in vacuo. The resulting residue was separate and purified by a thin-layer chromatography (ethyl acetate/hexane=1/2) to give 4.27 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([CH:33]=O)[CH2:29][CH2:28]1)#[N:26]>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([C:25]#[N:26])[CH2:28][CH2:29]1
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#C[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 103 %

Procedure:
A solution of 24.0 g of tetrabromomethane in 100 ml of methylene chloride was placed at -15° C. in a sulphonation flask under argon gasification and treated within 10 minutes with a solution of 38.0 of triphenylphosphine in 50 ml of methylene chloride. The clear orange solution was stirred at -10° C. for a further 10 minutes and subsequently a solution of 5.0 g of trans-4-cyanocyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise thereto at -5° C. within 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes, then poured into 1 l of 10% ethyl acetate/petroleum ether and freed from precipitated triphenylphosphine oxide by filtration. The concentrated filtrate was again digested with 500 ml of 10% ethyl acetate/petroleum ether, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (14 g) on silica gel with 10% ethyl acetate/petroleum ether gave 11.0 g of trans-4-(2,2-dibromovinyl)cyclohexanecarbonitrile which was still contaminated with triphenylphosphine. A second low-pressure chromatography of this material on silica gel with 3% ethyl acetate/petroleum ether gave 9.04 g (85%) of pure trans-4-(2,2-dibromovinyl)cyclohexanecarbonitrile, m.p. 77.5°-78.5° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:18]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:4][CH:5]=4)[C:11]=3[CH2:19]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cc1
Temperature: 150 °C
Yield: 24.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (700 mg, 3.4 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (1.5 g, 10.2 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.1 mmol). The mixture was heated in a sealed tube at 150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (340 mg, 26%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[CH2:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Cl:1][CH2:2][CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:8]=[CH:7][C:6]1[CH:9]=[CH:10][CH:3]=[CH:4][CH:5]=1
Reactant: C=Cc1ccc(CCl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C=Cc1ccccc1
Product: ClCC=Cc1ccccc1

Procedure:
According to the same manner as described in Example 6, p-chloromethylstyrene (82.5 g, 0.541 mole) and styrene (18.8 g, 0.181 mole) were polymerized by using azobis-iso-butyronitrile (1 g) to obtain a copolymer of chloromethylstyrene and styrene as white powder, yield 80%. The structure was confirmed by IR and NMR spectra.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([CH2:12][F:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CCOCC>[NH2:1][CH:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10](=[O:11])[CH2:12][F:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)CF
Agent: Cl
Solvent: CCOCC
Product: NC(Cc1ccccc1)C(=O)CF
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.1 %

Procedure:
To a solution of Boc-PheCH2F (0.75 g, 2.67 mmol) in anhydrous ether (5 mL) was added a saturated solution of HCl in ether (30 mL). The mixture was stirred vigorously at room temperature for 45 minutes. The suspension was filtered, washed with ether (10 mL), and pumped dry, to give a white solid (0.31 g, 54%). This material was immediately used in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:31]
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)-4-methoxybenzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:29]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[CH:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=5)[C:6]=4[CH:17]=3)=[CH:28][CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: Cc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cc32)cc1

Procedure:
The title compound, off-white solid (22 mg, 17%), MS (ISP) m/z=369.2 [(M+H)+], mp 149° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-p-tolyl-1H-benzo[d]imidazole (intermediate F) (100 mg, 348 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (93.3 mg, 453 μmol).
Reaction SMILES: C(N1[C:12]2[C:7](=[CH:8]C=CC=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCC(C)C>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:5][CH2:6][CH:7]([CH3:12])[CH3:8])[C:20](=[O:25])[C:19]2=[O:26]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Solvent: CC(C)CCBr
Product: CC(C)CCN1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
This compound was prepared in a similar method as 1-propylindoline-2,3-dione by reacting commercially available 5-chloro isatin (purchase from Fisher Scientific) with commercially available 1-bromo-3-methylbutane (purchase from Fisher Scientific). 1H NMR δ 7.57 (m, 2H), 6.85 (d, 1H), 3.73 (t, 2H), 1.57 (m, 3H), 1.00 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][C:13]3[CH:15]=[N:16][C:17](Cl)=[CH:18][C:12]=3[N:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][NH2:26]>[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][C:13]3[CH:15]=[N:16][C:17]([NH:26][CH3:25])=[CH:18][C:12]=3[N:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]2=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: CC(C)(C)N1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(Cl)cc21
Agent: [Cu]I
Product: CNc1cc2c(cn1)CN(c1ccc(F)c(N)c1)C(=O)N2C(C)(C)C
Temperature: 180 °C
Yield: 46 %

Procedure:
3-(3-Amino-4-fluorophenyl)-1-tert-butyl-7-chloro-3,4-dihydro-1H-pyrido[4,3-d]pyrimidin-2-one (2.0 g, 5.7 mmol), CuI (200 mg, 1.05 mmol) and methylamine (200 mL) were combined in a steel bomb and heated to 180° C. for 48 h. The reaction vessel was cooled to −78° C., unsealed, and warmed to RT. The reaction was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine (2×100 mL), dried (Na2SO4), concentrated and purified by neutral aluminum oxide column chromatography to provide 3-(3-amino-4-fluorophenyl)-1-tert-butyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (900 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.76 (s, 1 H), 6.91 (dd, J=11.1, 8.7 Hz, 1 H), 6.61 (dd, J=8.1, 2.4 Hz, 1 H), 6.35-6.32 (m, 3 H), 5.14 (s, 2 H), 4.29 (s, 2 H), 2.74 (d, J=4.8 Hz, 3 H), 1.55 (s, 9 H); MS (ESI) m/z: 344.0 [M+H]+.
Reaction SMILES: B(Cl)(Cl)Cl.C([NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[NH:27][N:26]=3)[C:21](/[CH:33]=[CH:34]\[CH3:35])=[CH:20][N:19]=2)=[CH:16][CH:17]=1)(=[O:12])=[O:11])(C)(C)C>C(Cl)Cl>[CH:30]1([C:28]2[NH:27][N:26]=[C:25]([NH:24][C:22]3[C:21](/[CH:33]=[CH:34]\[CH3:35])=[CH:20][N:19]=[C:18]([C:15]4[S:14][C:13]([S:10]([NH2:9])(=[O:12])=[O:11])=[CH:17][CH:16]=4)[N:23]=3)[CH:29]=2)[CH2:32][CH2:31]1
Reactant: C/C=C\c1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C/C=C\c1cnc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)[nH]n1
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
BCl3 (1 M in CH2Cl2, 3.28 mL, 3.28 mmol, 4.0 equiv.) was added to a stirred solution of (Z)—N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(prop-1-enyl)pyrimidin-2-yl)thiophene-2-sulfonamide (375.6 mg, 0.82 mmol, 1.0 equiv.) in CH2Cl2 (20 mL) at room temperature under nitrogen. The reaction mixture was stirred for 30 min and then quenched with aq. NaHCO3 in ice bath. The reaction mixture was extracted with ethyl acetate and washed with water, brine, dried and evaporated. The crude product was crystallized with THF/isopropyl to afford (Z)-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(prop-1-enyl)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 207) (255.1 mg, 77.4%). LC-MS (m/z)=403 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.76 (m, 2H), 0.95-1.00 (m, 2H), 1.79-1.81 (m, 2H), 1.90 (d, J=6.0 Hz, 1H), 1.93-1.97 (m, 1H), 5.60-6.04 (m, 0.6H), 6.26-6.31 (m, 0.4H), 6.46-6.49 (s, 1.5H), 6.79 (d, J=15.2 Hz, 0.4H), 7.57-7.59 (m, 1H), 7.74-7.79 (m, 3H), 8.19 (s, 0.6H), 8.39 (s, 0.4H), 8.94 (s, 0.5H), 9.33 (s, 0.3H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([C:35]([O:37]CC2C=CC=CC=2)=[O:36])[CH2:17][CH2:18][C@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:23]([O:22][C:20](=[O:21])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18][CH2:17][C:16]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1)[C:35]([OH:37])=[O:36])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cn1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cn1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
To a solution of 310 mg of 4-benzyl 1,4-di-tert-butyl (1S)-5-[5-(benzyloxy)pyridin-2-yl]-1-[(tert-butoxycarbonyl)amino]pentane-1,4,4-tricarboxylate (0.44 mmol) in methanol (10 mL) was added a 10% palladium on carbon hydrogenation catalyst (15 mg) at room temperature. The suspension was stirred for 3 h at room temperature under an atmosphere of hydrogen. The catalyst was removed by filtration and all volatiles were removed in vacuo. The crude product (234 mg, quantitative yield) was used in the next step without further purification.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([CH:17]([F:19])[F:18])=[CH:10][N:9]=1)=[O:7])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:19][CH:17]([F:18])[C:11]1[CH:12]=[C:13]([N+:14]([O-:16])=[O:15])[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ncc(C(F)F)cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)c1ncc(C(F)F)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
In a mixture of 5 ml DCM and 2.5 ml TFA was dissolved 345 mg (1.26 mmol) 5-difluoromethyl-3-nitro-pyridine-2-carboxylic acid tert-butyl ester and the reaction mixture was stirred for 4 h. Toluene was added and the solvents were evaporated to provide the title compound as colorless solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:18][CH2:19][CH3:20])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([S:15]([CH3:17])=[O:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:29])C=1.[NH4+].[OH-]>FC(F)(F)C(O)=O>[CH2:18]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([S:15]([CH3:17])(=[O:29])=[O:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C1CCc2cccc(S(C)=O)c2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C1CCc2cccc(S(C)(=O)=O)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a solution of 2-dipropylamino-8-methylsulfinyl-1,2,3,4-tetrahydronaphthalene (350 mg, 1.19 mMol) in trifluoroacetic acid (20 ml) was added a solution of metachloroperbenzoic acid (80%, 518 mg, 2.38 mMol) in trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 18 hours and poured over ice. The resulting mixture was made basic (NH4OH) and extracted well with dichloromethane. The organic extracts were combined, dried (NA2SO4) and concentrated in vacuo to give the crude title compound as a brown oil. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the desired product as a light orange oil (110 mg, 30%). The maleate salt was formed. Recrystallization (ethanol/diethyl ether) gave a colorless solid (70 mg, m.p.=113°-114° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][SH:23])[CH3:16].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:15]([CH:17]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][S:23][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:16]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Brc1ccc2c(ccc3ncnn32)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3ncnn32)c1
Temperature: 110 °C

Procedure:
8b (120 mg, 0.48 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (110 mg, 0.55 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed for 10 minutes with N2. iPr2NEt (0.16 mL, 0.89 mmol) was added, followed by Pd2dba3 (10 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol), and the mixture was degassed with N2 for an additional 10 minutes. The reaction was sealed and heated at 110° C. for 4 hours. The reaction was cooled to room temperature and purified by silica gel chromatography (25-100% EtOAc in hexanes) to give the desired product, 8e.