Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]3[O:40][CH:39]=[CH:38][C:37]=3[CH:41]=2)O1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:40]1[C:36]2[CH:35]=[CH:34][C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:41][C:37]=2[CH:38]=[CH:39]1
Reactant: CC1(C)OB(c2ccc3occc3c2)OC1(C)C
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4occc4c3)n2n1
Temperature: 110 °C
Yield: 34.8 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 80 mg, 0.232 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran (73.6 mg, 0.302 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 22 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.774 mL of 1,4-dioxane and 0.387 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (34.4 mg, 35%). 1H NMR (DMSO-d6) δ: 11.13 (s, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.89-8.00 (m, 4H), 7.78 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.10 (dd, 1H), 6.34 (s, 1H), 5.13 (s, 1H), 2.35 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 452.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[NH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[I:28]>C1COCC1>[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[CH:20][C:19]=1[I:28])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@H](Cc2ccccc2)N1Cc1cc(C(F)(F)F)ccc1I
Reaction time: 0.33 h

Procedure:
A stirred suspension of sodium hydride (60% in oil, 27 mg, 0.68 mmol) in THF (3 mL) was treated at 0° C. with (S)-4-benzyl-2-oxazolidinone (49 mg, 0.27 mmol) dissolved in THF (1 mL), under an atmosphere of N2. The reaction was stirred for 20 min and a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (100 mg, 0.27 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 18 h. The reaction was quenched with H2O (1 mL) and partitioned between EtOAc (80 mL) and H2O (25 mL). The aqueous phase was re-extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash silica-gel chromatography (0-30% EtOAc in hexanes gradient) to afford (4S)-4-benzyl-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one. Rf=0.45 (15% EtOAc/hexanes). LCMS 462 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.04 (d, J=8.2 Hz, 1H), 7.54 (br s, 1H), 7.33-7.27 (m, 5H), 7.11-7.10 (m, 2H), 7.32 (m, 1H), 4.80 (d, J=16.0 Hz, 1H), 4.49 (d, J=16.1 Hz), 4.28 (t, J=8.7 Hz, 1H), 4.25 (t, J=9.1, 4.8 Hz, 1H), 3.94 (m, 1H), 3.16 (dd, J=13.5, 4.8 Hz, 1H), 2.73 (dd, J=9.1, 4.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:2][CH2:3][CH2:4][C:5]#[N:8])=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC#N)cc2)c2ccccc21
Temperature: 80 °C

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was dissolved in DMF at room temperature and K2CO3 was added. 4-Bromobutylnitrile was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford the product.
Reaction SMILES: [CH2:1]([Mg:5][CH2:6][CH2:7]CC)[CH2:2][CH2:3][CH3:4].[CH2:10]([Al:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11]>CCCCCCC>[CH2:1]([Mg:5][CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH2:10]([Al:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11]
Reactant: CCCC[Mg]CCCC
Agent: CC[Al](CC)CC
Solvent: CCCCCCC
Product: CCCC[Mg]CC

Procedure:
In this case, the n-heptane solution of the complex consisting of di-n-butyl magnesium and tri-ethyl aluminum which was used in Example 51 was replaced with a reaction product obtained from 161 ml of an n-heptane solution of n-butyl ethyl magnesium (manufactured by Texas Alkyls Inc. of U.S.A., MAGALABEM, Mg concentration 0.65 mol/liter) and 4.3 ml of tri-ethyl aluminum. With the exception of this, a catalytic component was prepared and propylene was polymerized in exactly the same manner as in Example 1. The results of polymerization were: A=445, H.I.=94.8 and ρB=0.45.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:23]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])([CH2:39][O:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22]>ClCCl>[CH2:24]([C:23]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH3:63])([CH2:39][O:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38]
Reactant: COCCOCCOCCOCCOCC(COCCOCCOCCOCCOC)(COCCOCCOCCOCCOC)COCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCCOCCOCCOCC(COCCOCCOCCOCCOC)(COCCOCCOCCOCCOC)COCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Trifluoroacetic acid (TFA, 0.5 ml) and dichloromethane (0.5 ml) was added to 20 mg of 5. The mixture was shaken at room temperature for 1 h and the volatile materials was then removed at reduced pressure to give 18 mg of 6 as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH3:3].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:4]1[CH:5]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc(Br)ccc1OCc1ccccc1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCc1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of 3-propyl-4-benzyloxy-1-bromobenzene (1.0 g, 3.3 mmol), morpholine (0.5 g, 6.6 mmol), Pd(OAc)2 (0.036 g, 0.16 mmol), BINAP (0.082 g, 0.132 mmol) and cesium carbonate (1.50 g, 4.62 mmol) in toluene (134 mL) was degassed and purged with nitrogen. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and 10% aqueous citric acid. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated to an oil. The resulting oil was chromatographed on silica gel, using toluene with 5% ethyl acetate, to afford the title compound (1.03 g)
Reaction SMILES: [CH:1]([C:4]([S:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10])=O)([CH3:3])[CH3:2].C([N:18](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+].C(P(CCCC)CCCC)CCC>CC(C)=O.O.C1(C)C=CC=CC=1>[C:1](=[C:4]1[NH:18][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Sc1ccccc1C(=O)O
Reactant: CCN(CC)CC
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)=C1NC(=O)c2ccccc2S1
Temperature: -15 °C
Yield: 29.5 %

Procedure:
2-[(Isopropylcarbonyl)thio]benzoic acid (11.20 g, 50 mmol) was suspended in acetone (150 ml). While stirring under ice cooling, triethylamine (5.10 g, 50 mmol) and then ethyl chloroformate (6.68 g, 62 mmol) were dropwise added to the suspension. After stirring at the same temperature for an hour, an aqueous solution (15 ml) of sodium azide (5.00 g, 77 mmol) was dropwise added to the reaction mixture, followed by further stirring for an hour. The reaction mixture was diluted with water and the dilution was extracted with toluene (100 ml×3). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The toluene solution was cooled to about −15° C. and a solution (10 ml) of tributylphosphine (10.50 g, 52 mmol) in toluene was dropwise added to the solution. After completion of the dropwise addition, the reaction temperature was reverted to room temperature and the mixture was heated under reflux for 15 minutes. The reaction solution was concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl acetate to give the title compound (3.03 g, 30%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cccc(C)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)cccc1C(=O)O
Yield: 95 %

Procedure:
To a solution of 2 (1.19 mol) in a mixture of methanol (2 L) and water (0.5 L), potassium hydroxide pellets (100 gram, 1.5 mol) were added under cooling. The mixture was refluxed overnight and evaporated to dryness. The residue was dissolved in water (0.5 L) and acidified with HCl 6N. The product precipitated and 189 g of product was collected as white crystals. Yield 95%. 1H NMR (500 MHz, CDCl3, 25° C.) δ: 2.234 (s, 3H, CH3), 3.717 (s, 3H, OCH3), 7.062 (t, J=7.5, 1H, ArH), 7.365 (d, J=7.5, 1H, ArH), 7.496 (d, J=7.5, 1H, ArH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:12][S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:28](Br)[C:29]#[CH:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:27])[CH:4]([N:12]([S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[C:18]([CH3:25])[C:17]=1[CH3:26])(=[O:15])=[O:14])[CH2:30][C:29]#[CH:28])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCBr
Reactant: COC(=O)C(Cc1ccccc1)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCN(C(Cc1ccccc1)C(=O)OC)S(=O)(=O)c1c(C)cc(OC)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
A DMF (8 mL) solution of 2-(4-Methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-phenyl-propionic acid methyl ester (prepared according to example 2, step I) (200 mg) was cooled to 0° C. and then propargyl bromide (80%, 0.07 mL, 0.61 mmol) and Cs2CO3 (200 mg, 0.61 mmol) were added under an atmosphere of N2. The ice bath was removed and the reaction mixture was stirred at room temperature for 12 h. The mixture was partitioned between ether and water, the ether layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:3) as eluent to obtain 2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-prop-2-ynyl-amino]-3-phenyl-propionic acid methyl ester (185 mg, 85%) as a solid. 1H NMR (CDCl3, 400 MHz): δ7.20-7.17 (m, 3H), 7.10-7.08 (m, 2H), 6.56 (s, 1H), 4.42-4.29 (m, 3H), 3.86 (s, 3H), 3.56 (s, 3H), 3.32 (dd, 1H), 3.26 (dd, 1H), 2.66, 2.35 (2s, 6H), 2.21 (t, 1H), 2.08(s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH:6]1([C:9](Cl)=[O:10])[CH2:8][CH2:7]1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:9]([CH:6]1[CH2:8][CH2:7]1)=[O:10]
Reactant: CNOC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.79 mmol) and TEA (19.36 g, 191.32 mmol) were dissolved in CH2Cl2 (60 ml). Cyclopropanecarbonyl chloride (10 g, 95.66 mmol) was added dropwise at 0° C. After addition, the mixture was allowed to warm to 25° C. and stirred for 18 h. After the reaction completed, the solution was washed with H2O, saturated NaHCO3, 1 N HCl and brine. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to get N-methoxy-N-methylcyclopropanecarboxamide as a yellow oil. (8.6 g, yield 70%).
Reaction SMILES: C([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:30])=[O:5])=[CH:12][CH:11]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCN(c3ccc4ccccc4c3)CC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(NC2CCN(c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 110.4 %

Procedure:
A solution of (8) (0.067 g, 0.17 mmol) in HCl (10 mL, 4M in 1,4-dioxane) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was concentrated to give a white solid residue (0.065 g, 99%); 1H NMR (DMSO) δ 8.31 (s, 1H), 8.06 (m, 5H), 7.70 (d, 2H, J=8.7), 7.60 (m, 2H), 6.70 (d, 2H, J=8.8), 3.76 (m, 5H), 2.17 (m, 4H); 13C NMR (DMSO) δ 167.4, 151.2, 132.7, 131.2, 129.9, 128.0, 127.8, 127.4, 119.3, 117.4, 111.4, 66.3, 29.0; HRMS (FAB) m/z 347.1770 (M+H)+ (C22H22N2O2 requires 347.1760); Anal. (C22H22N2O2 ·2HCl) C, H, N.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][OH:17])[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][S:58]([CH3:57])(=[O:60])=[O:59])[CH:14]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCO)cn2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cn(CCOS(C)(=O)=O)cn2)n1
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 119e (65 mg, 0.10 mmol) in DCM (1.5 mL) was added DIPEA (71 μL, 0.41 mmol) followed by methanesulfonyl chloride (16 μL, 0.20 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.23 min, m/z 717 [MH+].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH:19]([OH:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[H-].[Na+].Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:21][CH:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19](=[O:20])[N:11]2[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[N:1]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2cnccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3cnccc3n2)CC1
Yield: 80.6 %

Procedure:
Following the procedure of Example 4 but starting with 2-(1,6-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (1.7 g.) in anhydrous tetrahydrofuran (17 cc.), sodium hydride (50% dispersion in mineral oil) (0.58 g.), 1-chlorocarbonyl-4-methylpiperazine (0.5 g.) in anhydrous tetrahydrofuran (5 cc.) and hexamethylphosphotriamide (4.5 cc.), a product (1.3 g.), melting at 215° C., is obtained. After washing with diisopropyl ether (30 cc.), this product is dissolved in methylene chloride (40 cc.). After filtration, the solution is concentrated to dryness to yield 3-(4-methylpiperazin-1-yl)carbonyloxy-2-(1,6-naphthyridin-2-yl)isoindolin-1-one (1 g.) melting at 215° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1.[B:38]1(B2OC(C)(C)C(C)(C)O2)[O:42]C(C)(C)C(C)(C)[O:39]1.C([O-])(=O)C.[K+]>CS(C)=O>[O:16]=[C:5]1[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=[C:2]([B:38]([OH:42])[OH:39])[CH:3]=[C:4]1[C:17]1[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]2[CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:19]=2[N:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccc(C(F)(F)F)cc3n2COCC[Si](C)(C)C)c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccc(C(F)(F)F)cc3n2COCC[Si](C)(C)C)c1=O
Temperature: 95 °C

Procedure:
6-Chloro-4-[6-trifluormethyl-1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one (prepared in analogy to example 15b), bis(pinacolato)diboron, (1,1′-bis(diphenylphosphine)ferrocene)-palladium(II) chloride-dichloromethane complex and potassium acetate are dissolved in DMSO. The solution is degassed with argon and heated at 95° C. for 2.5 hours. The reaction solution is filtered through silica gel, and the latter is washed with dichloromethane. The solvent is removed in a rotary evaporator, and the crude product is purified by RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)). MS (ES+) m/z 585 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](O)=[O:16].O.Cl>O1CCCC1>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16]
Reactant: O=C(O)Cc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccccc1F
Yield: 88.4 %

Procedure:
11.4 g lithium aluminum hydride were initially introduced into 100 ml analytical grade tetrahydrofuran, the mixture was heated to the reflux temperature under a nitrogen atmosphere, 50 g 2-fluorophenylacetic acid, dissolved in 400 ml analytical grade tetrahydrofuran, were added dropwise and the reaction mixture was heated for a further two hours. For working up, 72 ml water followed by 250 ml half-concentrated hydrochloric acid (16 per cent by weight) were added dropwise, while cooling in an ice-bath. The mixture was extracted twice with 250 ml diethyl ether each time, the combined extracts were washed twice with 100 ml sodium bicarbonate solution (5 per cent by weight) each time, dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 40.2 g 2-(2-fluorophenyl)ethanol were obtained.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][C:50]1[C:55]([NH2:56])=[CH:54][CH:53]=[CH:52][N:51]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:56][C:55]4[C:50]([O:49][CH3:48])=[N:51][CH:52]=[CH:53][CH:54]=4)=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: COc1ncccc1N
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2OC)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-methoxy-pyridin-3-ylamine (Fluorochem) to give the title compound. HR-MS (ES, m/z) calculated for C41H48Cl2N7O4 [(M+H)+] 772.314, observed 772.3138.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:8]=2[S:7](=[O:15])(=[O:14])[N:6]=[CH:5]1>C(O)(C)C>[CH3:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:8]=2[S:7](=[O:15])(=[O:14])[NH:6][CH2:5]1
Reactant: CN1C=NS(=O)(=O)c2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN1CNS(=O)(=O)c2ncccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.08 g of NaBH4 is added to a solution of 0.1 g of 4-methyl-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1- dioxide (Example 63) in 6 cm3 of isopropanol. The mixture is kept stirring at ambient temperature for 45 minutes. The solvent is then removed under partial vacuum and the residue is treated with 5 cm3 of water. The suspension obtained is adjusted to a pH of 7 and then extracted with chloroform (3 times 100 cm3). The organic phase is washed with water (25 cm3), dried (MgSO4) and then concentrated to dryness to provide the title compound.