Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:27][CH3:28])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cccnc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (1.8 mL, 13.0 mmol) was added to a mixture of N2-phenylpyridine-2,3-diamine (800 mg, 4.32 mmol), (S)-2-tertbutoxycarbonylaminobutyric acid (960 mg, 4.75 mmol), HOAt (650 mg, 4.75 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (910 mg, 4.75 mmol) in anhydrous DCM (25 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 16 h. After re-cooling to 0° C., additional amounts of (S)-2-tertbutoxycarbonylaminobutyric acid (610 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (580 mg), HOAt (410 mg) and triethylamine (1.0 mL) were added and stirring at RT continued for 1 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a dark oil. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method J): RT 2.67 min [M+H]+ 371.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][CH2:11][C:12]1[N:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([CH2:11][C:12]2[CH:17]=[N:16][C:15]([CH3:18])=[CH:14][N:13]=2)[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1cnc(CN)cn1
Solvent: O
Product: Cc1cnc(Cn2c(C)cc(O)cc2=O)cn1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (5.0 g, 0.04 mol) and 5-aminomethyl-2-methylpyrazine (5.0 g, 0.041 mol) in water (25.0 ml) was heated at 100° C. for 1 h under argon atmosphere. The reaction mixture was cooled, and filtered the yellow precipitate. It was washed with ethanol, and dried in vacuo to afford the title compound (5.8 g, 63%) as a pale yellow powder: 1H NMR (DMSO-d6/400 MHz) δ10.43 (br, 1H), 8.38 (d, 2H, J=5.2 Hz), 5.77 (d, 1H, J=2.0 Hz), 5.58 (d, 1H, J=2.0 Hz), 4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H); ESMS m/z 232 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:13][S:14]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])=[O:15]
Reactant: O=C(NCCO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCNC(=O)c1ccccc1

Procedure:
2-Benzamidoethyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (291 mg, 84%) from N-(2-hydroxyethyl) benzamide (245 mg, 1.30 mmol) and methanesulfonyl chloride (223 mg, 1.94 mmol). 1H NMR (CDCl3, 300 MHz) δ2.85 (s, 3H), 4.48 (t, 2H, J=9.5 Hz), 5.10 (t, 2H, J=10.2 Hz), 7.58-7.63 (m, 2H), 7.74-7.80 (m, 1H), 8.20-8.23 (m, 2H) ppm.
Reaction SMILES: C[CH:2]([CH:6]([C:26]1[CH:30]=[CH:29][N:28]([CH:31]([CH3:33])[CH3:32])[N:27]=1)[N:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:15]([O:24][CH3:25])=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].C1COCC1.[OH-].[Na+].Cl>CO>[CH:31]([N:28]1[CH:29]=[CH:30][C:26]([CH:6]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[C:15]([O:24][CH3:25])=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]4)[CH2:9][CH2:8]2)[CH2:2][C:3]([OH:5])=[O:4])=[N:27]1)([CH3:32])[CH3:33]
Reactant: COc1ccc2cccnc2c1N1CCCN(C(c2ccn(C(C)C)n2)C(C)C(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2ccn(C(C)C)n2)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
A 35 mL scintillation vial equipped with a magnetic stirrer was charged with (±)-methyl 3-(1-isopropyl-1H-pyrazol-3-yl)-3-[4-(7-methoxyquinolin-8-yl)-1,4-diazepan-1-yl]propanoic acid (450 mg, 1.0 mmol), THF (5 mL), MeOH (5 mL) and 1 N NaOH solution (6 mL, 6.0 mmol). The resulting suspension was stirred at 40° C. overnight (18 h). 2 N HCl (ca. 3 mL) was added to bring the pH to 7 and the mixture extracted with 10% MeOH in CH2Cl2 containing 0.5% aqueous NH4OH (3×50 mL). The combined organic layer was concentrated and dried in vacuo to afford the title compound (360 mg, 82%) as a light yellow foam. MS (ES) m/z 438.4 (M+Hf).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[Se:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:24]2[CH2:25][CH:21]([CH2:22][CH2:23]2)[C:20](=[O:26])[CH:19]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[Se:9][C:10]([CH2:13][O:14][C:18]3[CH:24]4[CH2:25][CH:21]([CH2:22][CH2:23]4)[C:20](=[O:26])[CH:19]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1C=C(Cl)C2CCC1C2
Reactant: OCc1cnc(-c2ccc(Cl)cc2)[se]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C=C(OCc2cnc(-c3ccc(Cl)cc3)[se]2)C2CCC1C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.7 %

Procedure:
To a solution of [2-(4-chlorophenyl)selenazol-5-yl]methanol (300 mg, 1.1 mmol) in dry tetrahydrofuran (5 ml) is added, in one portion, sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol). The reaction mixture is stirred for 5 minutes at room temperature and 4-chlorobicyclo[3.2.1]oct-3-en-2-one (172 mg, 1.1 mmol) is added in one-portion. The reaction mixture is stirred at room temperature overnight. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-[2-(4-chlorophenyl)selenazol-5-ylmethoxy]bicyclo[3.2.1]oct-3-en-2-one (275 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][S:19]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)(=[O:21])=[O:20]>CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:24][CH2:23][O:22][S:19]([CH3:18])(=[O:21])=[O:20])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CS(=O)(=O)OCCOS(C)(=O)=O
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOS(C)(=O)=O)c(C=O)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0° C. was added 27,3 g (125 mmol) 1,2-bis-methanesulfonyloxy-ethane ((J. Med. Chem.; 47; 17; (2004); 4300-4315) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70° C. for 5 h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulfate and evaporated. The crude product was purified by silica column chromatography (gradient ethylacetate:hexane 1:6, ethyl acetate→1:2). The desired product 4a was obtained in 78% yield (21.4 g, 78 mmol) as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[CH3:19][NH2:20].CO>>[Cl:8][C:6]1[CH:7]=[C:2]([NH:20][CH3:19])[N:3]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:5]=1
Reactant: CN
Reactant: COc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Solvent: CO
Product: CNc1cc(Cl)nc(SCc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
4,6-dichloro-2-(4-methoxybenzylsulfanyl)pyrimidine (3.0 g, 10 mmol) was dissolved in a 40% methylamine-methanol solution (20 ml) and stirred overnight at room temperature. The solvent was distilled away under reduced pressure, water was added and extracted twice with ethyl acetate. After combining the organic layers and washing with a saturated saline solution, it was dried with MgSO4 and the solvent was distilled away under reduced pressure. Separation and purification were performed by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain 1.64 g (56% yield) of 4-chloro-2-(4-methoxybenzylsulfanyl)-6-methylaminopyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]([CH3:14])=[C:4]2[S:5][CH:6]=[CH:7][C:3]=12.C([Li])(C)(C)C.[CH3:20][Sn:21](Cl)([CH3:23])[CH3:22]>O1CCCC1>[CH3:14][C:8]1[C:4]2[S:5][C:6]([Sn:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][C:3]=2[C:2]([CH3:1])=[C:10]2[S:11][C:12]([Sn:21]([CH3:23])([CH3:22])[CH3:20])=[CH:13][C:9]=12
Reactant: Cc1c2ccsc2c(C)c2ccsc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1c2cc([Sn](C)(C)C)sc2c(C)c2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A dry 250-mL three-neck round bottom flask was flushed with N2 and was charged with 4,8-dimethylbenzo[1,2-b:4,5-b′]dithiophene (1.02 g, 4.70 mmol) and anhydrous tetrahydrofuran (THF) (75.0 mL, 0.01 M) via deoxygenated syringe. The reaction flask was cooled to −78° C. and a 1.3 M solution of tert-butyllithium in hexanes (9.00 mL, 23.0 mmol) was added drop-wise via deoxygenated syringe. After 30 minutes of stirring at −78° C., the solution was chilled to 0° C. and stirring was continued for 5 minutes, at which point the reaction mixture was cooled back to −78° C. A 1 M solution of trimethyltin chloride (19.0 mL, 37.0 mmol) in hexanes was added to the reaction flask dropwise and stirring continued for 30 minutes at −76° C. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. As the reaction was completed, cool DI water (10 mL) was slowly added to the reaction flask. Then, the reaction mixture was poured into 50 mL of cool water and extracted with MTBE (100 mL) three times. The combined organic layer was washed with water two times and dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified by precipitation into methanol from a THF solution to yield white solid (1.90 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N+:6]([O-:20])[CH:7]=1
Reactant: COC(=O)c1ccc(F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.5 %

Procedure:
Methyl 5-fluoropicolinate (440 mg, 2.836 mmol) was dissolved in CHCl3 (10 ml), followed by addition of mCPBA (954 mg, 4.254 mmol), and then the resulting mixture was stirred at room temperature for 15 hours. A saturated aqueous Na2S2O3 solution (15 ml) was added to the resulting reaction liquid, followed by extraction with 5% MeOH/MC (30 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (2% MeOH/MC), to obtain 318 mg of colorless oil (66%).
Reaction SMILES: [F:1][CH:2]([F:6])[C:3](O)=[O:4].C(Cl)(=O)C(Cl)=O.Cl.[CH3:14][NH:15][O:16][CH3:17].CC1C=CC=C(C)N=1>ClCCl>[CH3:14][N:15]([O:16][CH3:17])[C:3](=[O:4])[CH:2]([F:6])[F:1]
Reactant: O=C(O)C(F)F
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CON(C)C(=O)C(F)F
Temperature: 35 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of difluoroacetic acid (4.1 g, 42.7 mmol) in dry dichloromethane (80 ml), under N2, was treated with oxalyl chloride (5.69 g, 44.8 mmol). After stirring at 35° C. for 3 h, the reaction was cooled to 0° C. and treated with N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.2 mmol), then cooled to -20° C., and treated dropwise with 2,6-dimethylpyridine (19.86 ml, 171 mmol). The reaction was allowed to warm up to room temperature over 2 h then quenched by the addition of ice and water. Orthophosphoric acid (2M) was added until the aqueous layer reached pH4. The aqueous and organic phases were separated and the organic layer was washed with 2M orthophosphoric acid (2×50 ml). The organic layer was dried (Na2SO4) then concentrated in vacuo and the residue was distilled to afford the title compound (D5) as a clear oil (3.72 g, 63%) b.p. 60° C. at 1.5 mm Hg (Kugelrohr).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[CH:61]=[CH:60][N:59]=[C:58]([NH2:62])[N:57]=2)=[CH:51][CH:50]=1>ClCCCl>[NH2:62][C:58]1[N:57]=[C:56]([NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH:46][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:50][CH:51]=2)[CH:61]=[CH:60][N:59]=1
Reactant: NCCc1ccc(Nc2ccnc(N)n2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4ccnc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), DIPEA (0.134 mL, 0.76 mmol) and N4-[4-(2-aminoethyl)phenyl]pyrimidine-2,4-diamine (49 mg, 0.15 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F-:13].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [F-]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
To a solution of 4-methoxy-benzenesulfonyl chloride (1.0 g, 4.8 mmol) in acetonitrile (20 mL) was added KF (563 mg, 9.7 mmol) and the resulting mixture was stirred for 16 h at room temperature. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (780 mg) as a colourless oil. 1H NMR (CDCl3): 7.97 (2H, d), 7.09 (2H, d), 3.94 (3H, s).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.[Na+].[I-:20].C(O)(=O)C>C(#N)C>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([OH:17])=[O:16])[C:3]([OH:18])=[C:2]([I:20])[CH:1]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 864.1 %

Procedure:
20 mg (0.08 mmol) of diflunisal, 14 mg (0.093 mmol) of NaI and 30 mg (0.13 mmol) of CAT dissolved in 1040 μl of acetonitrile and 52 μl of acetic acid are placed in a 25 ml flask. It was stirred for 1.5 hr at room temperature. The reaction was monitored by HPLC until the consumption of starting product was observed and 96% of iodinated product was detected. The solution was then acidified to pH=1.0 with a 5% solution of HCl and extracted with ethyl acetate. The organic phases were combined and washed with a solution of sodium thiosulphate and then dried over anhydrous magnesium sulphate. The solvent was removed at low pressure and a crude of 98% purity was obtained and then purified by chromatography on silica gel. 260 mg (86% yield) of the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH2:21][CH2:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:19][C:20]3[CH2:21][CH2:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC1=Cc2ccccc2CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc2c(s1)CCN(CC1=Cc3ccccc3CC1)CC2
Yield: 29 %

Procedure:
Prepared from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 3-chloromethyl-1,2-dihydronaphthalene (prepared from 1,2-dihydronaphthalene, paraformaldehyde and concentrated hydrochloric acid) in anhydrous dimethylformamide for 2 hours at 50° C. Yield: 29% of theory, Melting point: 158°-160° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:13])=[CH:5]2
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
5-Chloroindole-2-carboxylic acid (391 mg, 2 mmol), tert-Butyl [(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]carbamate (497 mg, 2 mmol), DIPEA (350 μL, 2 mmol) and HOBT (270 mg, 2 mmol) were dissolved in DCM (10 mL), stirred for 5 mins, then EDCI (479 mg, 2.5 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (25 mL) was added and the organic solution washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (800 mg, 94%) as a pale brown foam.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)=[O:4].[NH2:19][C@H:20]([CH2:23][CH3:24])[CH2:21][OH:22]>C(OCC)(=O)C>[OH:22][CH2:21][C@H:20]([NH:19][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=1)=[O:4])[CH2:23][CH3:24]
Reactant: CS(=O)(=O)c1cc(NC(=O)CCl)cc([N+](=O)[O-])c1
Reactant: CC[C@@H](N)CO
Solvent: CCOC(C)=O
Product: CC[C@H](CO)NCC(=O)Nc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
2-Chloro-N-(3-methanesulfonyl-5-nitro-phenyl)-acetamide (750 mg; 2.56 mmol) was diluted in 40 of ethyl acetate, (R)-(−)-2-amino-1-butanol (1.01 ml; 10.25 mmol) was added and the reaction mixture was stirred at 75° C. overnight. The solvent was concentrated under vacuum and the crude was purified by flash chromatography (Isolute Silica cartridge 10 g; eluent: Dichloromethane:MeOH=99:1). 380 mg (1.10 mmol; 43% yield) of the desired 2-((R)-1-Hydroxymethyl-propylamino)-N-(3-methanesulfonyl-5-nitro-phenyl)-acetamide were obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:35])=[O:34]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Product: CC(C)CS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(2-Methyl-propane-1-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and 2-methyl-propane-1-sulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Cl:15][C:16]1[C:17](F)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][CH:19]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 2 g, 9.99 mmol), 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (CAS number 72537-17-8; 1.44 ml, 10.98 mmol), DIPEA (1.744 ml, 9.99 mmol) in DMSO (35 ml) was heated at 140° C. for 5 hours. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-15% ethyl acetate/petrol) and then by column chromatography (silica, 0-10% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:9]=[C:8]([CH3:10])[O:7][N:6]=1.O.[NH2:13][NH2:14]>C(O)CCC>[CH3:10][C:8]1[O:7][N:6]=[C:5]([CH2:4][C:3]([NH:13][NH2:14])=[O:2])[CH:9]=1
Reactant: COC(=O)Cc1cc(C)on1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1cc(CC(=O)NN)no1
Yield: 90 %

Procedure:
As described for example 112a, (5-methyl-isoxazol-3-yl)-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was heated under reflux for 90 min. Evaporation of all volatiles afforded the title compound as a white solid (yield: 90%). 1H-NMR (300 MHz, DMSO): δ=2.36 (d, J=0.7 Hz, 3H), 3.39 (s, 2H), 4.25 (s, 2H), 6.13 (d, J=0.7 Hz, 1H), 9.27 (s, 1H).