Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:16]2[C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:9]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.C(Cl)Cl.CCOCC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[N:9]=[C:10]3[C:16]=2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: OCCCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 12 %

Procedure:
5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester (Example 82, 0.009 g) was dissolved in 9:1 Et2O/CH2Cl2 (3 mL) and the solution was added slowly to a stirred suspension of lithium aluminum hydride (2 mg) in 5 mL of anhydrous Et2O. After stirring at RT for 6 h, the reaction was quenched with 2 mL of water. The mixture was treated with 2 mL of 1 N NaOH, followed by another 2 mL of water. The mixture was then filtered through diatomaceous earth. The organic layer was separated, dried over MgSO4, and concentrated. After further drying via vacuum line, the resulting oil was dissolved in 2 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 4 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.001 g of the title compound as a colorless oil. MS (ESI): exact mass calculated for C18H24ClN3O, 333.16; found, m/z 334.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.52 (m, 2H), 7.32-7.30 (m, 2H), 3.95 (t, J=7.1 Hz, 2H), 3.44 (t, J=6.6 Hz, 2H), 3.13-3.09 (m, 2H), 3.03-3.00 (m, 2H), 2.98-2.95 (m, 2H), 2.61-2.58 (m, 2H), 1.70-1.64 (m, 2H), 1.40-1.35 (m, 2H), 1.20-1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][N:11]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:18][OH:19])[CH3:2].[H][H]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:18][OH:19])[CH3:2]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COCCCCN1C(=O)CCC[C@@H]1CO
Reaction time: 3 h
Yield: 100.6 %

Procedure:
Palladium on carbon (10 wt. %, 15 mg) was added to a solution of [(Z)-4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid ethyl ester (290 mg, 1.02 mmol) in EtOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 3 h. The reaction mixture was filtered through celite, washing with EtOH, and the filtrate was concentrated in vacuo to afford 295 mg (quant. crude) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9](I)=[CH:10]3)[C:6]=2[CH:16]=1.C[Si](N[Si](C)(C)C)(C)C.C[N:28](C)[CH:29]=[O:30]>>[Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:29]([NH2:28])=[O:30])=[CH:10]3)[C:6]=2[CH:16]=1
Reactant: CN(C)C=O
Reactant: Fc1cc2c(cc1Br)-c1nc(I)cn1CCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Into a 5000-mL pressure tank reactor (10 atm) purged and maintained with an inert atmosphere of nitrogen was placed 9-Bromo-8-fluoro-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (204 g, 498.79 mmol, 1.00 equiv), HMDS (403.5 g, 2.50 mol, 5.00 equiv), Pd(PPh3)Cl2 (11 g, 25.02 mmol, 0.05 equiv), and N,N-dimethylformamide (3 L). To the above CO (10 atm) was introduced in. The resulting solution was stirred overnight at 80° C. and quenched by the addition of 5 L of water. The solids were collected by filtration. The crude product was re-crystallized from 800 mL of EA. The mixture was stirred at 50° C. for 3 h. The solids were collected by filtration, washed with 3×100 mL of EA and dried to afford 48.5 g (30%) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a yellow solid. LC-MS: 326 [M+H]+; 1H-NMR (DMSO, 300 MHz, ppm): δ 8.75 (d, J=8.4 Hz, 1H), 7.79 (s, 1H), 7.61 (s, 1H), 7.16-7.11 (m, 2H), 4.49-4.50 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44][CH2:45][O:46][CH2:47]Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][O:20][CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCOC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 250 mg, 0.57 mmol), diisopropyl ethyl amine (238 μL, 1.37 mmol) and 2-methoxyethoxymethyl chloride (MEMCI) (78 μL, 0.68 mmol) were mixed in dry DMF (5 mL) and stirred at room temperature overnight. More diisopropyl ethylamine (250 μL, 1.44 mmol) and MEMCl (100 μL, 0.88 mmol) were added and it was stirred for another 6 hours. Again MEMCl (90 μL, 0.79 mmol) was added and it was stirred overnight. The solvent was evaporated under reduced pressure. Chromatography on silica gel with acetone/hexanes 3:1 and precipitation from dichloromethane/hexanes gave the product as off-white solid (261 mg).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH:5]([O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[CH2:6]>>[CH:8]1([O:7][CH:5]=[CH:6][C:1]([Cl:4])=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Cl)Cl
Reactant: C=COC1CCCCC1
Product: O=C(Cl)C=COC1CCCCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
50 g (0.5 mol) of phosgene were condensed into a stirred apparatus fitted with a -78° C. dry-ice condenser. 50.5 g (0.4 mol) of cyclohexyl vinyl ether were subsequently added dropwise at 20° C. over the course of 3 hours. The mixture was subsequently stirred at 50° C. for a further 5 hours. The excess phosgene was expelled by means of nitrogen, and the crude product was worked up by distillation at 110° C./2.5 mbar, giving 66.4 g (88%) of valuable product.
Reaction SMILES: [C@@H:1]1([N:9]2[C:13]3[N:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[NH:16][C:17](=[O:18])[C:12]=3[C:11]([I:25])=[CH:10]2)[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.CO.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([O:8][CH2:7][C@H:5]2[O:6][C@@H:1]([N:9]3[C:13]4[N:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[NH:16][C:17](=[O:18])[C:12]=4[C:11]([I:25])=[CH:10]3)[CH2:2][C@@H:3]2[OH:4])([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:31]2[CH:48]=[CH:49][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)C(=O)Nc1nc2c(c(I)cn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(I)c4c(=O)[nH]c(NC(=O)C(C)C)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
Compound (59) is repeatedly dried by evaporating off anhydrous pyridine. 400 mg (0.87 mmol) of compound (59) which has been dried in this way are dissolved in 5 ml of anhydrous pyridine. After adding 4,4′-dimethoxytrityl chloride (328 mg, 0.95 mmol) at room temperature, the reaction mixture is stirred overnight. MeOH (3 ml) and 5% aq. NaHCO3 (30 ml) are then added. The aqueous phase is extracted 3 times with CH2Cl2. The organic phase is dried (Na2SO4) and evaporated, and the residue is subjected to flash chromatography (column: 10×5 cm, solvent CH2Cl2/acetone, 9:1). Isolating the material from the main zone affords the colorless, amorphous title compound (61). (600 mg, 91%). 1H-NMR ([D6] DMSO: δ=1.13 (m, 4 CH3), 2.24 (m, H—C(2′)), 2.77 (m, CH), 3.12 (m, H—C(5′)), 3.75 (s, 2 CH3O), 3.93 (m, H—C(4′)), 4.35 (m, H—C(3′)), 5.30 (d, 3′-OH), 6.39 (dd, H—C(1′)), 6.86-7.39 (m, aromatic H+H—C(6)), 11.54, 11.82 (2s, 2 NH). Anal. calculated for C36H37JN4O7 (764.6): C 56.55, H 4.88, N 7.33: found C 56.42, H 4.82, N 7.30.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4](F)=[O:5].[OH2:17]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:17])=[O:5]
Reactant: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Reactant: O
Product: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Reaction time: 24 h

Procedure:
A suspension of crude 2,3-dichloro-4-trifluoromethoxybenzoyl fluoride (2 g, containing mixed antimony halides) in water was stirred vigorously for 24 hours. The mixture was extracted with dichloromethane and filtered. The organic layer was washed with hydrochloric acid (2M), aqueous sodium chloride solution and extracted into sodium carbonate solution (2M). The aqueous extract was acidified to pH1 and the solid was filtered off and washed with water to give 2,3-dichloro-4-trifluoromethoxybenzoic acid (0.6 g) as a white solid mp 123°-126° C.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33]C)=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:35])[C@H:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])=[CH:23][CH:22]=1)[NH:9][C:10](=[O:19])[C:11]1[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 50.4 %

Procedure:
BBr3 (1 mL, 1M in CH2Cl2) was added to a CH2Cl2 (10 mL) solution of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine methyl ester (0.215 g) at 0°0 C. with stirring and the solution was slowly warmed to room temperature. The mixture was stirred for 3 h and quenched with EtOH. The solvent was removed and the residue was taken up in EtOAc. The solution was washed with satd. NaHCO3 followed by brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: hexanes/EtOAc 2:1) to yield 0.105 g of N-(2,6-dichlorobenzoyl)-4-(2-hydroxyphenyl)-L-phenylalanine methyl ester. ESMS: m/z 444 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([OH:27])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:9])=[O:8])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([O:27][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN([C@@H]1CCCCC(O)C1)S(=O)(=O)c1ccc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN([C@@H]1CCCCC(OS(C)(=O)=O)C1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (R)—N-naphthalene-2-sulfonyl (3-hydroxy-cyclohepty)glycine ethyl ester (0.90 g, 2.22 mmol) in dichloromethane (30 mL) at 0° C. is added triethylamine (0.463 mL, 3.3 mmol), methane sulfonyl chloride (0.269 g, 2.35 mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol), and the reaction is allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate. The solvents are removed in vacuo, and the residue is purified by column chromatography (35% hexanes-ethyl acetate) to afford the title compound as a colorless oil (0.95 g, 88% yield). LCMS (m/z): 484.17 (M+1), 482.16 (M−1).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)[C:3]([NH:5]C(=O)C1C=CC=CC=1)=[S:4].[OH-].[Na+].Cl>CO>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)[C:3]([NH2:5])=[S:4]
Reactant: CN(C(=S)NC(=O)c1ccccc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(N)=S)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 48.4 %

Procedure:
To a 100 mL round bottom flask containing MeOH (23 mL) was added N-(methyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamothioyl)benzamide (2.8 g, 5.63 mmol) and sodium hydroxide (5.6 mL of a 2 N solution, 11.3 mmol), and the solution was heated at 65° C. for 3.5 hours. Another 20 mL (40 mmol) of 2N NaOH was then added and heating was continued for 6 hours. Upon cooling the solution was neutralized by addition of 2N HCl, and the resulting yellow solid was collected by vacuum filtration to give 1-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)thiourea as a yellow solid (1.073 g, 47%): mp 142-152° C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.36-8.24 (m, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.46-7.33 (m, 4H), 5.62 (s, 2H), 3.73 (s, 3H); ESIMS m/z 393 ([M+H]+).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][N:15]2[CH2:19][CH:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=3)[CH2:21][N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH2:30][C:31]([OH:33])=[O:32])[CH2:13][CH2:14]2)[CH2:7][CH2:6]1)([OH:3])=[O:2].[C:34](Cl)(Cl)=[S:35]>Cl.C(Cl)(Cl)Cl>[C:1]([CH2:4][N:5]1[CH2:18][CH2:17][CH2:16][N:15]2[CH2:19][CH:20]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]=[C:34]=[S:35])=[CH:27][CH:28]=3)[CH2:21][N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH2:30][C:31]([OH:33])=[O:32])[CH2:13][CH2:14]2)[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(CC2CN3CCCN(CC(=O)O)CCN(CCCN(CC(=O)O)CC3)C2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)CN1CCCN2CCN(CC(=O)O)CCCN(CC1)CC(Cc1ccc(N=C=S)cc1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 143 %

Procedure:
A solution of compound 28 (1.21 g, 1.75 mmol) in 0.5 M HCl (50 mL) was carefully added to thiophosgene (CSCl2) (4.03 mL, 6.04 g, 52.5 mmol) in CHCl3 (50 mL). The reaction mixture was stirred for 5 hours at room temperature and the layers were allowed to separate. The aqueous layer was removed and the organic CHCl3 layer was then washed with water (2×50 mL). The combined aqueous layers were washed with CHCl3 (3×50 mL) to remove unreacted thiophosgene. Finally, the aqueous layer was lyophilized to afford white crystalline solid 29 (1.26 g, 98% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:32]([O:34]C)=O)=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:36].CO>C1COCC1>[C:32]([C:16]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[N:17]=1)(=[O:34])[NH2:36]
Reactant: N
Reactant: COC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (1015 mg, 2.0 mmol) in THF (15 mL) at room temperature under argon was added 7M ammonia in methanol (4.3 mL, 30 mmol). The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo. The crude product 1.0 g (100%) was used directly to next step. MS (ESI) 437 (M+H-tBu).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1>>[CH3:21][CH:22]1[NH:23][CH2:24][CH2:25][N:26]([C:2]2[C:7]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:27]1
Reactant: CC1CNCCN1
Reactant: COc1ccccc1OCC(C)Oc1nccnc1Cl
Product: COc1ccccc1OCC(C)Oc1nccnc1N1CCNC(C)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(2-methoxyphenoxy)-1-methylethoxy]pyrazine* (150 mg, 0.51 mmol) and 2-methylpiperazine (260 mg, 2.6 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (65%) of the title product. HRMS m/z calcd for C19H26N4O3M)+358.2005, found 358.2018. Anal. (C19H26N4O3) C, H, N.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH:1]2[N:12]3[C:13]4[C:9]([CH:10]5[CH2:17][NH:16][CH2:15][CH2:14][CH:11]53)=[CH:8][CH:7]=[CH:6][C:5]=4[CH2:4][S:3][CH2:2]2)=[CH:24][CH:25]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Reactant: Fc1ccc(OCCCCl)cc1
Product: Fc1ccc(OCCCC2CSCc3cccc4c3N2C2CCNCC42)cc1

Procedure:
The title compound of EXAMPLE 5 was prepared from (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole and 1-(3-chloropropoxy)-4-fluorobenzene following the procedure described in EXAMPLE 4. 1H NMR (CDCl3, 300 MHz): δ 7.0-6.78 (m, 6H), 6.65 (t, 1H, J=7.3 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.84 (dd, 2H, J=16.4 Hz), 3.59 (m, 2H), 3.25 (m, 2H), 3.15 (m, 2H), 2.85 (m, 2H), 2.65 (m, 2H), 2.45 (m, 4H), 2.30 (m, 2H) ppm. LRMS (ES)+: 399 (M+H)+.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1)=O.C([NH:26][NH2:27])(=O)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C(O)(=O)C.C(O)C>[C:11]([C:9]1[O:10][C:6]([C:4]2[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:27][N:26]=2)=[CH:7][CH:8]=1)([OH:13])=[O:12]
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2F)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1

Procedure:
2.5 g (11 mmol) of 5-(2-fluorobenzoyl)furan-2-carboxylic acid, 3.28 g (24 mmol) of benzhydrazide and 2 drops of glacial acetic acid in 50 ml of ethanol were heated under reflux for 10 h. The mixture was subsequently concentrated using a rotary evaporator and the residue was taken up in water, made alkaline using 2 N NaHCO3 solution and extracted with ethyl acetate. The aqueous phase was made acidic using 2N hydrochloric acid and extracted with ethyl acetate. The combined organic phases were dried and concentrated using a rotary evaporator. The residue was dissolved in 25 ml of THF, 2.74 g (24.2 mmol) of potassium tert-butoxide were added and the mixture was stirred at reflux temperature for 1.5 h. After cooling, the mixture was concentrated using a rotary evaporator and the residue was taken up in 1 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The precipitate that resulted when the aqueous phase was acidified was filtered off with suction, washed with water and dried in a vacuum drying cabinet at 40° C. This gave 1.88 g (75%) of the title compound. m.p.: 205° C. (decomp).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: COc1ccc(Oc2cccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-methoxyphenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-methoxyphenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[S:16][C:15]([C:17]([O:19]C)=O)=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[CH:10]=[N:11][C:6]2=[CH:5][CH:4]=1.[NH3:33]>CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:33])=[O:19])=[C:14]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:13]=3)[CH:10]=[N:11][C:6]2=[CH:5][CH:4]=1
Reactant: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: COc1ccc2ncn(-c3cc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2n1
Temperature: 130 °C
Reaction time: 10 h

Procedure:
A mixture of 0.74 g of methyl 5-(5-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B7b) and 200 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 130° C. for 10 h. The reaction mixture was allowed to cool down to room temperature and concentrated to about half of the volume. The precipitated solid was filtered, dissolved in 4 ml methanol/DMSO (1:1) and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)). After lyophilization the obtained solid was crystallized with dichloromethane/n-hexane to give the title compound.