Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1N)([CH3:3])[CH3:2].N([O-])=O.[Na+].S(=O)(=O)(O)N.[BrH:20]>O>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[Br:20])([CH3:3])[CH3:2]
Reactant: Br
Reactant: CC(C)c1ccccc1N
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccccc1Br
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To an initial charge of 65 ml of 48% aqueous HBr are added, in portions, 13.5 g [0.1 mol] of 2-isopropylaniline. The resulting thick suspension is stirred at 80° C. for 15 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the thin suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 70° C., of 13.9 g [0.05 mol] of FeSO4×7H2O in 65 ml of 62% aqueous HBr. The reaction mixture is then stirred for another 1 hour without further heating and allowed to cool to room temperature, and admixed with 125 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 18.75 g of an oil which, according to GC, contains 82.3% 2-isopropylbromobenzene (77.5% of theory).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[F:27].[OH-].[Na+]>O1CCCC1>[F:26][C:22]1[C:21]([F:27])=[CH:20][CH:25]=[CH:24][C:23]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Fc1cccc(Br)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Temperature: 25 °C
Yield: 69.8 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (1.22 g, 5 mmol) was dissolved in 20 ml of tetrahydrofuran under stirring, and added with 1-bromo-2,3-difluoro-benzene (0.97 g, 5 mmol), tetrakis (triphenylphosphine)palladium (0.17 g, 0.15 mmol) and sodium hydroxide solution (7 ml, 2 mol/L) under an argon atmosphere. Upon completion of the addition, the reaction system was stirred at 75° C. in an oil bath overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature and extracted with ethyl acetate (20 ml×3). The combined organic extracts were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4-(2,3-difluoro-phenyl)-1H-indole 6c (800 mg, yield 70%) as a white solid.
Reaction SMILES: [OH-].[Na+].C(#N)C.[NH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>O>[CH3:16][N:17]([CH3:22])[S:18]([C:12]1[C:10]2[NH:11][C:7]([NH2:6])=[N:8][C:9]=2[CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CN(C)S(=O)(=O)c1cccc2nc(N)[nH]c12
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of sodium hydroxide (1.8 g) in water (9 mL) add acetonitrile (44 mL). To this solution, add 2-aminobenzimidazole (3.0 g, 22.5 mmol) and dimethylsulfamoyl chloride (2.4 mL, 22.5 mmol). Stir the reaction mixture at room temperature, overnight. Then, cool the mixture at 0° C. and the product crystallized from solution. Filter the product and dry it in vacuum to provide 5.0 g (90% yield) of the title compound as a white solid. MS (ES+): m/z=241.1 (M+H)+
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14]CC(O)=O)[C:9]1=[O:19].C(Cl)Cl>CN(C)C=O>[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14][CH2:1][C:2]([Cl:4])=[O:3])[C:9]1=[O:19]
Reactant: CN1C(=O)CN(CCC(=O)O)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)CN(CCC(=O)Cl)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
340.9 g (2.6857 mol) of oxalyl chloride are added dropwise over the course of 18 minutes at an internal temperature of 19°-23° C. to a solution of 100.0 g (0.537 mol) of 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionic acid, synthesized as described in Example 6, 350 ml of methylene chloride and 1 ml of dimethyl formamide, and the mixture is subsequently stirred at room temperature for 5 hours and 10 minutes. When the reaction is complete, the reaction mixture is evaporated in a rotary evaporator, the residue is stripped 3 times at 50° C. under reduced pressure with 100 ml of toluene in each case, and the residue is dried at 60° C./0.1 mbar to constant weight, giving 106.1 g (97.3% of theory) of solid, brownish 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionyl chloride having the following analytical data:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[N:41][CH:42]=2)O1.N#N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:37]4[CH:38]=[CH:39][C:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[N:41][CH:42]=4)=[C:3]([C:17]#[C:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of compound 18b (0.50 g, 1.2 mmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (0.44 g, 1.4 mmol) in dioxane/water (4:1 v/v, 5 mL) was purged with N2. Dichloro(diphenylphosphinoferrocene)palladium (42 mg, 0.06 mmol) was then added, followed by solid Cs2CO3 (0.94 g, 2.9 mmol). The reaction mixture was stirred at 85° C. for 1 h under N2, and allowed to cool to rt. EtOAc (100 mL) was then added. The organic layer was washed with water (2×50 mL), and brine (100 mL), dried over Na2SO4, filtered and concentrated to give a residue which was purified by flash column chromatography on silica gel (0-40% EtOAc/heptanes) to give compound 38a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H29N7O3: 548.2 (M+H). found: 548.1.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-chloro-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone (1 g, 3.9 mmol) was dissolved in 10 ml of dry THF and 7.8 ml of a 1M solution of dimethylamine in THF (7.8 mmol) were added. This reaction mixture was stirred at ambient temperature for 24 h. The solvent was removed under reduced pressure and the residue was crystallized from diethyl ether to give the expected compound 2-(dimethylamino)-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone in the form of a brown solid (m.p. 130-132° C.).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][C:9]([OH:11])=O)=[C:6]([CH3:12])[NH:5][N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH3:12][C:6]1[C:7]([CH2:8][C:9]([NH:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:11])=[C:3]([CH3:2])[NH:4][N:5]=1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1n[nH]c(C)c1CC(=O)O
Agent: Cl
Product: Cc1n[nH]c(C)c1CC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 50 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 258, (S)-2-(2-(3,5-dimethyl-1H-pyrazol-4-yl)acetamido)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (70 mg, 50%). 1H-NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.40-7.25 (m, 6H), 7.15-6.90 (m, 7H), 6.50 (m, 1H), 4.79-4.73 (m, 1H), 4.63 (m, 2H), 3.80-3.50 (m, 4H), 2.20 (s, 6H). MS (EI) for C29H28F2N4O4 found 535 (MH+).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[OH-].[Na+].[O:8]=[C:9]1[C:18](=[O:19])[NH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:20](Cl)(=[O:22])=[O:21])[CH:15]=2)[NH:10]1>O>[Br:2][CH2:3][CH2:4][NH:5][S:20]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:8])[C:18](=[O:19])[NH:17]2)(=[O:21])=[O:22]
Reactant: NCCBr
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2ccc(S(=O)(=O)NCCBr)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.9 %

Procedure:
20.49 g (0.1 mole) of 2-bromoethylamine hydrobromide and 4.00 g (0.1 mole) of sodium hydroxide are dissolved in 60 ml of water, and 7.82 g (0.03 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added to the solution, and the mixture is stirred at room temperature for 6 hours. Then it is allowed to stand for 16 hours. The separated crystals are filtered, washed successively with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from the solution with water. Thus 3.44 g (33%) of N-(2-bromoethyl)-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 261-266° C.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1C(OC(C)(C)C)=O)([O-:3])=[O:2].C(Cl)[Cl:25]>>[ClH:25].[N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10](=[O:23])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)([O-:3])=[O:2]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCCCCO[N+](=O)[O-]
Product: Cl
Product: O=C(OCCCCO[N+](=O)[O-])[C@@H]1CCCN1

Procedure:
N-Boc-L-proline 4-nitrooxybutyl ester (1.24 g, 3.7 mmol) was dissolved in CH2Cl2 (20 mL) and HCl gas was bubbled into the solution for 2 hours. Then the mixture was concentrated, affording L-proline 4-nitrooxybutyl ester hydrochloride as a clear oil (1.00 g, quantitative).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[C:26](=[O:31])[CH2:27][C:28](=[O:30])[CH:29]=4)[CH2:21]3)[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>CO>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@H:22]3[C@@H:18]([CH2:19][N:20]([C:25]4[CH:26]([OH:31])[CH2:27][C:28](=[O:30])[CH:29]=4)[CH2:21]3)[C@@H:17]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3=O)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3O)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as a mixture of diastereomers from the intermediate of step A according to the procedure of Example 6, step C (NaBH4 in methanol). 1H-NMR (CDCl3): rotamers; δ: 7.71 (1 H, s), 7.23 (2 H, s), 7.00 (2 H, m), 6.93 (2 H, t, J=8.2 Hz), 4.88-4.65 (2 H, m), 4.46 (1 H, m), 4.07 (0.5 H, m), 3.83 (0.5 H, m), 3.55 (1 H, m), 3.35 (1 H, m), 3.28 (1 H, m), 2.97 (2 H, m), 2.92 (1 H, m), 2.58 (1 H, m), 2.43 (1 H, m), 2.25 (1 H, m), 2.13 (1 H, m), 2.05-1.85 (2 H, m), 1.70-1.55 (2 H, m), 1.30 (3 H, 2d, J=6.0 Hz). MS: (MH)+ 572.5 The diastereomers were separated by HPLC on CHIRACEL OD column eluting with hexanes/EtOH (85/15) to afford the individual diastereomers.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3I)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C-:22]#[N:23].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([C:22]#[N:23])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Reactant: [C-]#N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 160 °C
Yield: 78.9 %

Procedure:
A mixture of (R)-indan-1-yl-(5-iodo-quinolin-2-yl)-amine (example 6, step A) (1.44 g, 3.73 mmol), zink cyanide (482 mg, 4.1 mmol) and tetrakis-(triphenylphosphine)-palladium (431 mg, 0.37 mmol) in DMF (20 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (diethyl ether/hexane) to yield 2-((R)-indan-1-ylamino)-quinoline-5-carbonitrile as light yellow solid (840 mg, 79%). M.p. 150° C.; MS: m/e=286.2 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].N1C=CC=CC=1.[C:17](Cl)(Cl)=[O:18].C1(C)C=CC=CC=1>C(Cl)Cl>[O:18]=[C:17]=[N:6][C@H:5]([C:4]([O:3][CH3:2])=[O:10])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C(C)C
Temperature: 0 °C

Procedure:
A mixture of L-valine methyl ester hydrochloride (10.0 g, 59.9 mmol), DCM (300 mL), and pyridine (19.3 mL, 240 mmol) was cooled in an ice/salt bath and a solution of 20% phosgene in PhMe (35.6 mL, 719 mmol) added dropwise, maintaining the reaction temperature below 5° C. during the addition. A white suspension resulted and after 1.5 hours, the reaction mixture was poured into ice-cold 1M HCl and extracted with DCM (2×500 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO4, and evaporated. Flash column chromatography on silica (95 hexanes/5 EtOAc) gave the title compound as a colorless oil (6.43 g). 1H NMR (CDCl3 500 MHz) δ 3.94 (d, J=4.0 Hz, 1H), 3.82 (s, 3H), 2.24 (m, 1H), 1.03 (3, J=7.0 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H) ppm.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.O[O:23][S:24]([O-:26])=O.[K+].[CH3:28]C(C)=O.O>>[CH3:28][S:24]([C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)(=[O:26])=[O:23]
Reactant: CSc1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Reactant: O=S([O-])OO
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
A mixture of (5-(2-(methylthio)pyrimidin-4-yl)thiophen-2-yl)(morpholino)methanone (200 mg) and oxone (2 g) in 60 mL of acetone-water (1:1) was stirred at rt for 24 h. The mixture was concentrated in vacuo to remove the acetone. The white precipitate was filtered, washed with water and dried to give the title compound (183 mg, 83%). MS (M+H)+ 354.
Reaction SMILES: [OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.S(=O)(=O)(O)O.[CH2:41](O)[CH3:42]>>[OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH2:41][CH3:42])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@]3(O)CC[C@@H](C(=O)O)C(C)(C)C3)s2)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1CC[C@@](O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reaction time: 16 h
Yield: 83 %

Procedure:
(1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (100 mg, 0.197 mmol) was dissolved in ethanol (3 ml) and concentrated sulfuric acid (10.52 μl, 0.197 mmol) added. The reaction mixture was stirred for 16 hours. The reaction mixture was extracted with ethyl acetate (3×) and washed with saturated aqueous sodium bicarbonate. Solvent evaporation gave the title compound (88 mg, 0.165 mmol, 83% yield). ESI: [M+H]+ m/z 535.2. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.82 (d, J=4.9, 1H), 7.93 (d, J=9.6, 2H), 7.46 (s, 1H), 7.27 (d, J=4.9, 1H), 7.14 (s, 1H), 4.07 (dt, J=10.8, 17.9, 2H), 2.31 (s, 3H), 2.05 (s, 3H), 1.96-1.78 (m, 3H), 1.65 (m, 2H), 1.18 (m, 3H), 1.09 (s, 3H), 0.97 (s, 3H). rhSYK activity=+++
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](=[O:14])([O-])[O-].[Na+].[Na+].[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:2][N:6]1[C@H:5]2[C@@:17]([CH3:21])([C:17]3[CH:21]=[CH:9][C:8]([C:2]4[S:3][C:4]5[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=5[N:6]=4)=[CH:7][C:18]=3[CH2:19][CH2:4]2)[CH2:18][CH2:19][C:11]1=[O:14]
Reactant: Clc1nc2ccccc2s1
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4nc5ccccc5s4)cc3CC[C@@H]12

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-chlorobenzothiazole (110 mg, 0.65 mmol), 0.65 mL of aqueous 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 18 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg /45%) of the title compound as an amorphous solid. mp 207°-212°. FDMS: m/e=362. α[D]589 =+88.83 (c=0.60, chloroform).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:20]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+]>>[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:20]=1[CH2:21][N:17]([CH2:21][C:20]1[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:19]=1[F:18])[C:15]1[CH:14]=[CH:13][C:12]2[NH:8][CH:9]=[N:10][C:11]=2[CH:16]=1
Reactant: Fc1cc(F)c(CBr)cc1F
Reactant: CC(C)(C)OC(=O)n1cnc2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(F)c(CN(Cc2cc(F)c(F)cc2F)c2ccc3[nH]cnc3c2)cc1F

Procedure:
The compound was synthesized starting from N1-Boc-benzimidazol-5-amine (233 mg; 1 mmol; 1 eq.), 2,4,5-trifluorbenzylbromide (563 mg; 2.5 mmol; 2.5 eq.) and K2CO3 (345 mg; 2.5 mmol; 2.5 eq.) according to method 4; Yield: 0.172 (40.9%); MS m/z: 422.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.68 (s, 4H); 6.74 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.78 (br s, 1H); 7.23-7.29 (m, 2H); 7.39 (d, 1H, 3J=8.9 Hz); 7.51-7.56 (m, 2H); 7.97 (s, 1H); 12.03 (br s, 1H); HPLC (METHOD [A]): rt 16.46 min (100%)
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:17]=1.N([C:40]([O:42][CH2:43][CH3:44])=[O:41])=NC([O-])=O.CO>CN(C=O)C>[CH2:43]([O:42][C:40]([CH2:16][CH2:17][N:5]1[C:4](=[O:6])[CH:3]=[CH:2][C:1]1=[O:7])=[O:41])[CH2:44][CH2:8][CH3:9].[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1C=CC(=O)N1
Reactant: CCOC(=O)N=NC(=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Solvent: CO
Product: CCCCOC(=O)CCN1C(=O)C=CC1=O
Reaction time: 0.25 h

Procedure:
2 g of maleimide-styrene copolymer are dissolved in 25 ml of DMF, 3 g of triphenylphosphine and 1.8 ml of ethyl azodicarboxylate are added, and the mixture is stirred for 15 minutes, during which slight warming occurs. 1.5 ml of L-(-)-butyl lactate are then added, and the mixture is stirred at room temperature for 20 hours, giving a clear, red-brown solution, which is poured into 300 ml of methanol. A milky-white precipitation of the polymer is obtained. Since the substance has a tacky consistency, it is separated off by centrifugation. After repeated washing with methanol and centrifugation, the product is dried at 70° C. in a drying cabinet. Yield 2.5 g. The polymer exhibits a rotation value of [α]D20 =+6.7° in the DMF solution.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:26]([O:28][C:29]([C:31]1[N:32]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH:59]([CH3:61])[CH3:60])=[CH:54][CH:53]=2)[C:33]2[C:38]([C:39]=1C=O)=[CH:37][C:36]([C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][N:43]=1)=[CH:35][CH:34]=2)=[O:30])[CH3:27].O.[CH3:63]N(C=O)C>>[CH2:26]([O:28][C:29]([C:31]1[N:32]([C:52]2[CH:53]=[CH:54][C:55]([O:58][CH:59]([CH3:60])[CH3:61])=[CH:56][CH:57]=2)[C:33]2[C:38]([C:39]=1[CH:63]=[CH:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:37][C:36]([C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:44][N:43]=1)=[CH:35][CH:34]=2)=[O:30])[CH3:27]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c(C=O)c2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=Cc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(F)(F)F)cn3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Carbethoxymethylene)triphenylphosphorane (330 mg, 0.95 mmol) was added to a suspension of 3-formyl-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)indole-2-carboxylic acid ethyl ester (427 mg, 0.95 mmol; see step (b) above) in DMF (15 mL) and the mixture was stirred at rt for 3 h. Another portion of (carbethoxymethylene)triphenylphosphorane (165 mg, 0.47 mmol) was added and the stirring continued for 12 h. The mixture was poured into H2O and extracted with EtOAc. The combined extracts were washed with H2O, brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 386 mg (80%).