Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH2:21][O:22][C:23](ON1C(=O)CCC1=O)=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH2:21][O:22][C:23]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(OCOC(=O)c1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCOC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]methyl benzoate (587 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 7 (445 mg, 66% yield) a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.83-0.95 (br. m, 2H), 1.16-1.39 (br. m, 3H), 1.65-1.72 (br. M, 2H), 1.82-1.91 (br. m, 2H), 2.09 (tt, J=12.4, 3.6 Hz, 1H), 2.81-2.88 (br. m, 2H), 5.88 (s, 2H), 7.50-7.57 (m, 2H), 7.61 (t, J=6.0 Hz, 1H), 7.65-7.70 (m, 1H), 7.93-7.97 (m, 2H), 11.96 (br. s, 1H). MS (ESI) m/z 336.01 (M+H)+; 333.98 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35]Br)=[CH:29][CH:28]=2)=[O:26])=[C:23]([OH:39])[CH:22]=1>>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][C:21]2[CH:38]=[CH:37][C:24]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:1][C:2]4[CH:3]=[CH:4][C:5]([C:8]5[O:9][C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[N:12]=5)=[CH:6][CH:7]=4)=[CH:29][CH:28]=3)=[O:26])=[C:23]([OH:39])[CH:22]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C(c1ccc(OCCBr)cc1)c1ccc(OCCBr)cc1O
Product: O=C(c1ccc(OCCOc2ccc(-c3nc4ccccc4o3)cc2)cc1)c1ccc(OCCOc2ccc(-c3nc4ccccc4o3)cc2)cc1O

Procedure:
The 2-(4-hydroxyphenyl) benzoxazole was reacted with 4,4'-bis(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce Compound IV.
Reaction SMILES: [OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]([O:13]C)=[O:12])=[CH:5]1.[OH-].[Na+].Cl>O1CCOCC1.CO>[OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]1
Reactant: COC(=O)c1ccc(=O)n(C[C@@H](C)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](O)Cn1cc(C(=O)O)ccc1=O
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A solution of (R)-methyl 1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (508 mg, 2.405 mmol) in 1,4-dioxane (12 mL) and MeOH (4.00 mL) was treated with aqueous sodium hydroxide, 5.0 M (0.962 mL, 4.81 mmol). The reaction was stirred at 23° C. After 20 h, the reaction was neutralized to pH=6.0 with 2 N HCl, and concentrated in vacuo. The residue was azeotroped with toluene (3×10 mL), suspended in a 1:1 MeOH:DCM solution (25 mL), and the white NaCl residue was removed by filtration. The filtrate was concentrated, affording (R)-1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid as a white solid. MS (ESI pos. ion) m/z: 198.1 (M+1).
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17]([C:21]#[C:22][CH2:23][CH:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32]C)=O)[CH2:26][CH2:25]4)[N:18]=[C:19]([NH2:20])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:34])[C@@H:7]1[OH:35])=[O:5].CO.[NH3:38]>>[CH2:2]([NH:3][C:4]([CH:6]1[CH:7]([OH:35])[CH:8]([OH:34])[CH:9]([N:11]2[CH:12]=[N:13][C:14]3[C:15]2=[N:16][C:17]([C:21]#[C:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH:27]([C:30](=[O:32])[NH2:38])[CH2:28][CH2:29]2)=[N:18][C:19]=3[NH2:20])[O:10]1)=[O:5])[CH3:1]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Reactant: N
Solvent: CO
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CCC4CCC(C(N)=O)CC4)nc32)C(O)C1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a sealed tube containing 10 mL of saturated MeOH/NH3 solution was added 5 mg (0.01 mmol) of ATL146e. The flask was sealed and allowed to stir at 25° C. for 48 hours. The vessel was cooled to 0° C., opened, and the ammonia removed by bubbling N2 for 1 hour. The remaining solvent was then removed in vacuo to yield 4.0 mg (83%) of JR3055 as a white solid after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) δ 8.41 (s, 1H), 5.98 (d, J=7.2 Hz, 1H), 4.65 (dd, J=7.3 Hz, 4.8 Hz, 1H), 4.41 (d, J=2.0 Hz, 1H), 4.28 (dd, J=4.6 Hz, 2.0 Hz, 1H), 3.35 (m, 2H), 2,37 (d, J=6,4 Hz, 2H) 2.10 (m, 1H), 1.90 (m, _H), 1.53 (m, _H_), 1.23 (m, 13H), 1,12 (t, J=7.3 Hz, 3H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 472.3 (MH+, 100), 299.4(10).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16]>C1C=CC=CC=1.C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: N#CCC#N
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A mixture of 1-(4-Nitro-phenyl)ethanone (10 g, 60.5 mmol), malononitrile (4 g, 60.5 mmol), NH4OAc (4.66 g, 121 mmol) in benzene (100 mL) and acetic acid (6.4 mL) was refluxed overnight using a Dean Stark to collect water. The reaction was allowed to cool to r.t., partitioned between water and EtOAc (3×). the combined organic were washed with brine, dried (Na2SO4), concentrated and purified via silica gel chromatography eluting with 3 to 1 hexanes:EtOAc to give 3.71 g (29%) of the title compound. Rf=0.22 (4:1 hexanes: EtOAc).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:14]3OCC[O:15]3)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>C(O)C.O.O1CCCC1.S(=O)(=O)(O)O>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Sc2cccc(C3OCCO3)c2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=Cc1cccc(Sc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
2-(3-Phenylsulfanyl-phenyl)-[1,3]dioxolane described in Preparation Example 91 (396 mg, 1.53 mmol) was dissolved in a mixture solution of ethanol (5 mL), water (5 mL), tetrahydrofuran (5 mL) and sulfuric acid (1 mL), and the solution was stirred for 2.5 hours under reflux. The reaction solution was cooled to 0° C., an aqueous solution of saturated sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (323 mg, 1.51 mmol, 98%) was obtained as a colorless oil.
Reaction SMILES: [C:1]12([CH2:15][CH:14]([NH:16][C:17](=[O:32])[NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4C(OC)=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[OH-].[Na+].O>CO>[NH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:17]([NH:16][CH:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:7][C:1]4([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:15]3)=[O:32])[CH:27]=[CH:26][CH:25]=2)[CH:21]=[N:22]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CC4(CCCCC4)Oc4ccccc43)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1cccc2[nH]ncc12)NC1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The product from Example 1C (4.06 mmol) was suspended in methanol (20 mL) and was treated with 5N methanolic NaOH (3.3 mL, 16.5 mmol). The mixture was stirred at room temperature for 45 min, then it was poured into H2O (100 mL). The precipitate that formed was collected by filtration and was air-dried to afford the title compound as an off-white solid, 794 mg (43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 13.01 (br, 1H), 8.67 (s, 1H), 8.06 (s, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.23 (J=7.8 Hz, 1H), 7.16 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.90 (td; J=7.5, 1.0 Hz; 1H), 6.80 (dd; J=7.9, 1.0 Hz; 1H), 6.72 (d, J=8.1 Hz, 1H), 4.98 (m, 1H), 2.24 (m, 1H), 1.33-1.82 (m, 1H). MS (ESI+) m/z 377 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][N:13]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=2)=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11]1
Reactant: NNc1cc(C2CCC2)c(Cl)nn1
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Product: Oc1ccc(C=NNc2cc(C3CCC3)c(Cl)nn2)cc1
Yield: 83.2 %

Procedure:
3-Chloro-4-cyclobutyl-6-hydrazinopyridazine (0.50 g, 2.5 mmol) and 4-hydroxybenzaldehyde (0.31 g, 2.5 mmol) were stirred in 0.2M hydrochloric acid (15 ml) for 2 hours. The precipitated imine was then collected by filtration and dried to give the title compound (0.63 g, 83%). MS (ES+) 305 [MH]+, 303 [MH]+.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:3][CH:2]=1.[Cl:31][C:32]1[C:33]([OH:43])=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=[C:36]([Cl:38])[CH:37]=1.CCN(CC)CC>C(Cl)Cl>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[S:39]([C:34]2[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([Cl:31])[C:33]=2[OH:43])(=[O:40])=[O:41])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl 3-((biphenyl-4-ylmethylamino)methyl)benzylcarbamate (2.42 g, 6.01 mmol) in CH2Cl2 (30.0 mL) was added a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (1.65 g, 6.31 mmol) in CH2Cl2 (8.0 mL) at ice bath temperature followed by Et3N (2.5 mL, 18.0 mmol). The reaction mixture was stirred at ice bath temperature for 1.5 h and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 eluting with CH2Cl2 to 8% of ethyl acetate in CH2Cl2 to give the product as a white glassy solid (2.78 g, 72.5%). 1H NMR (CDCl3): δ 9.18 (bs, 1H), 7.59-7.38 (m, 9H), 7.28-7.21 (m, 4H), 7.06 (m, 2H), 4.48 (s, 2H), 4.43 (s, 2H), 4.25 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[C:6]1[CH:7]=[C:8]([C:12]([CH3:24])([CH3:23])[CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([CH3:11])[N:10]=1)C.COC(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH:5]([C:6]1[CH:7]=[C:8]([C:12]([CH3:24])([CH3:23])[CH2:13][NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]([CH3:11])[N:10]=1)=[O:4]
Reactant: CCOC(OCC)c1cc(C(C)(C)CNC(=O)c2ccccc2)n(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cn1nc(C=O)cc1C(C)(C)CNC(=O)c1ccccc1
Reaction time: 8 h
Yield: 76.5 %

Procedure:
Hydrochloric acid (40 mL of 1 M) was added to a solution of N-[1-(5-diethoxymethyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide (8.7 g, 24 mmol) in tetrahydrofuran (40 mL), and the reaction was stirred for ten minutes. tert-Butyl methyl ether and 2 M aqueous sodium carbonate (20 mL) were added. The aqueous layer was extracted twice with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate and filtered. Hexane was added, and the cloudy mixture was stored overnight in the refrigerator. Crystals formed and were isolated in two crops by filtration to provide 5.24 g of N-[1-(5-formyl-2-methyl-2H-pyrazol-3-yl)-1,1-dimethylethyl]benzamide as a white powder, mp 150-151° C.
Reaction SMILES: [Li]CCCC.C(S)C1C=CC=CC=1.C([C@@H]1COC(=O)N1[C:27]([C@@H:29]1[CH2:38][CH2:37][C:32]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:31][C@H:30]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:28])C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:41]([O:40][CH2:39][C@H:30]1[C@H:29]([CH2:27][OH:28])[CH2:38][CH2:37][C:32]2([O:33][CH2:34][CH2:35][O:36]2)[CH2:31]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCC2(C[C@H]1COCc1ccccc1)OCCO2
Agent: SCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OC[C@@H]1CCC2(C[C@H]1COCc1ccccc1)OCCO2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of n-BuLi (2.4 M in hexanes, 75 mL) was added slowly to a solution of benzyl mercaptan (25 mL, 210 mmol) in THF (250 mL) at 0° C. The resulting pale-yellow solution was stirred at 0° C. for 15 min prior to the introduction of (4R)-benzyl-3-({(7R,8R)-7-[(benzyloxy)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}carbonyl)-1,3-oxazolidin-2-one (64.2 g, 138 mmol) as a solution in THF (250 mL). After 30 min, a solution of LiAlH4 (1.0 M in THF, 150 mL) was slowly added to the reaction mixture with continued stirring at 0° C. for 30 min. Ice water (15 mL) was then slowly added to destroy excess hydride followed by 6M HCl (110 mL) to pH 4. The mixture was extracted with two portions of ethyl acetate and the combined organics were washed with saturated aqueous NaCl and dried over Na2SO4. Concentration in vacuo and flash chromatography of the residue on silica gel eluting with 20/80 acetone/benzene afforded {(7R,8R)-7-[(benzyloxy)methyl]-1,4-dioxaspiro[4.5]dec-8-yl}methanol as a faint-yellow, thick syrup. 1H NMR (500 MHz, d6-acetone) δ 7.36 (4H, m), 7.29 (1H, m), 4.50 (2H, q, J=9.6 Hz), 3.90 (4H, s), 3.61 (1H, m), 3.52-3.42 (3H, m), 3.43 (1H, t, J= 5.5 Hz), 1.88-1.72 (4H, m), 1.55-1.41 (4H, m).
Reaction SMILES: [Mg].BrC(Br)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].[F-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCc1ccc(Br)cc1
Agent: CC(Br)Br
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
To a solution of magnesium (896 mg) in tetrahydrofuran (20 ml) was added dibromoethan (0.1 ml), and the mixture was stirred at room temperature for 15 minutes. Thereto was added dropwise a solution of 1-bromo-4-ethylbenzene (5.7 g) in tetrahydrofuran (20 ml), and subsequently, the mixture was stirred at room temperature for one hour. The reaction mixture was cooled to −78° C., and thereto was added dropwise tributyltin chloride (9.49 g). The mixture was stirred at the same temperature for 30 minutes, and then at room temperature for one hour. To the reaction mixture were added 10% aqueous potassium fluoride solution and ethyl acetate, and the mixture was stirred at room temperature for 30 minutes. Insoluble materials were filtered off. The organic layer of the filtrate was washed with water and brine successively, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by alumina column chromatography (hexane) to give the desired tri-n-butyl(4-ethylphenyl)tin (10.7 g) as colorless oil. EI-Mass m/Z 337 (M-Bu).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[F:19])=[CH:4][C:3]=1[Cl:21].[Cl:22][C:23]1[C:36]([N:37]=[C:38]=S)=[C:35]([Cl:40])[CH:34]=[CH:33][C:24]=1[CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].CC(C)N=C=NC(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2[C:11]([F:19])=[CH:12][C:13]3[N:17]([CH3:18])[C:38]([NH:37][C:36]4[C:35]([Cl:40])=[CH:34][CH:33]=[C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]=4[Cl:22])=[N:16][C:14]=3[CH:15]=2)=[O:20])=[CH:4][C:3]=1[Cl:21]
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(F)cc21

Procedure:
The title compound is prepared from N-(4-fluoro-3-chloro-phenyl)-2-fluoro-4-methylamino-5-amino-benzoic acid amide and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to examples 7b/7c.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:2]12.C(N(CC)CC)C.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>ClCCl>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[C:22]([S:26]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([OH:10])[CH2:9][C@@H:2]3[CH2:1]2)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O[C@H]1C[C@@H]2CNCCN2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCN2C[C@@H](O)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (7S,8aR)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 17D, 5 g, 21.52 mmol) and solvent 2,2,2-trifluoroethanol (50 mL) were added to 20% palladium hydroxide on carbon, wet (0.500 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. To a solution of the above crude (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol (1.0 g, 7 mmol) and triethylamine (1.13 g, 11.2 mmol) in dichloromethane (40 mL) was slowly added a solution of 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.712 g, 7 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature for 4 hours. The solution was concentrated, diluted with ethyl acetate (100 mL), washed with water (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol=10:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.58 (m, 2H), 1.97 (m, 2H), 2.10-2.35 (m, 3H), 2.90 (m, 1H), 3.20 (m, 1H), 3.62 (m, 1H), 3.77 (m, 1H), 4.14 (m, 1H), 4.80 (m, 1H), 7.92 (m, 2H), 8.10 (m, 2H); MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[C:15]([NH:20][C:21]1[NH:22][CH:23]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[C:25]=1[C:26]([NH2:28])=[O:27])(=[O:19])[CH:16]([CH3:18])[CH3:17]>O1CCCC1>[C:15]([NH:20][C:21]1[NH:22][CH:23]=[C:24]([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:13]([NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])=[O:14])=[CH:33][CH:34]=2)[C:25]=1[C:26]([NH2:28])=[O:27])(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 44.8 %

Procedure:
0.076 cm3 (0.436 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 25° C. to 0.125 g (0.436 mmol) of 2-isobutyrylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide in solution in 15 cm3 of tetrahydrofuran. After stirring for 17 hours at a temperature in the region of 25° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is then diluted in 40 cm3 of ethyl acetate and then washed with 40 cm3 of water. The organic solution is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is crystallized from 8 cm3 of a cyclohexane/ethyl acetate mixture (70/30 by volume). After filtration and drying, 0.096 g of 2-isobutyrylamino-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-3-carboxamide is obtained in the form of a cream solid melting at 196° C. IR (KBr), 3472; 3384; 1667; 1594; 1546; 1443; 1340; 1313; 1198; 1167; 1120; 1070; 937 & 614 cm−1. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm), 1.17 (d, J=7.0 Hz, 6H); 2.61 (m, 1H); 5.62 (broad m, 1H); 6.40 (d, J=2.5 Hz, 1H); 7.00 (broad m, 1H); 7.30 (d, J=9.0 Hz, 2H); 7.39 (m, 1H); 7.49 (m partially masked, 1H); 7.51 (d, J=9.0 Hz, 2H); 8.62 (dd, J=2.5 and 7.5 Hz, 1H); 8.99 (broad s, 1H); 9.32 (broad s, 1H); 10.95 (broad s, 1H); 11.45 (broad s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14]O>ClCCl>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[CH2:14][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)c(F)cc1Br
Solvent: ClCCl
Product: Fc1cc(Br)c(CCl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
146 μl of thionyl chloride in 2.5 ml of dichloromethane are added dropwise to 300 mg of (2-bromo-4,5-difluorophenyl)methanol in 2.5 ml of dichloromethane, and the mixture is stirred at 25° C. for 2 h. The mixture is evaporated to dryness in vacuo, the residue is taken up in 10 ml of toluene, and the operation is repeated. The residue is employed in the subsequent reactions without further treatment.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[O:17][CH2:16]4)=[CH:11][CH:10]=2)O1.I[C:30]1[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:9]2[CH:10]=[CH:11][C:12]([C:15]34[CH2:20][CH2:19][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:21][CH2:22]3)[O:17][CH2:16]4)=[CH:13][CH:14]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)CO2
Reactant: Nc1ccc(I)cn1
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(N)nc4)cc3)(CC1)CO2
Reaction time: 8 h

Procedure:
The title compound was prepared analogous to Example 4, Step 1 starting from methyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (200 mg, 0.52 mmol) and 5-iodopyridin-2-amine (137 mg, 0.62 mmol). The reaction was performed at 80° C. for overnight. After workup and column purification afforded the title compound as off-white solid after drying (133 mg, 58% yield). LC/MS, ESI-MS(+):353.3, RT: 1.12 (Condition E).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2ccn(Cc3ccc([N+](=O)[O-])cc3)c2c1

Procedure:
1-(4-Nitrobenzyl)-1H-indole-6-carboxylic acid methyl ester was prepared from 1H-indole-6-carboxylic acid methyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 5.75 (s, 2H), 6.66(dd, J=3.1, 0.6 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.60 (t, J=2.8 Hz, 1H), 7.79 (d, J=3.1 Hz, 1H), 8.07 (s, 1H), 8.15 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.28 (d, J=8.7 Hz, 2H); MS (ESI) m/z 311 (MH+); 309 ([M−H]−).