Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2/[CH:28]=[CH:29]/OCC)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:34])[C:19](=[O:33])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.BrC1C(NC2(C)CN(C(OC(C)(C)C)=O)C2)=CC2N3C(C)C(=O)NN=C3COC=2C=1.C([SiH](CC)CC)C.[C:72]([OH:78])([C:74]([F:77])([F:76])[F:75])=[O:73]>>[F:75][C:74]([F:77])([F:76])[C:72]([OH:78])=[O:73].[CH3:34][CH:18]1[N:17]2[C:16]3[CH:15]=[C:14]4[C:27]([CH2:28][CH2:29][N:13]4[C:10]4([CH3:12])[CH2:11][NH:8][CH2:9]4)=[CH:26][C:25]=3[O:24][CH2:23][C:22]2=[N:21][NH:20][C:19]1=[O:33]
Reactant: CCO/C=C/c1cc2c(cc1NC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Agent: CC1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc4c(cc3N21)N(C1(C)CNC1)CC4
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-[7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (prepared from tert-butyl 3-((8-bromo-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)-3-methylazetidine-1-carboxylate (Preparation #18) using the similar procedure detailed in Example #148, Step H) 0.65 g, 1.378 mmol) in TFA (4 mL) was stirred at ambient temperature for 20 min. Triethylsilane (4.8 g, 41.4 mmol) was added and the reaction mixture was stirred for 24 h. The solvent was removed in vacuo to give 1-methyl-10-(3-methylazetidin-3-yl)-5,8,9,10-tetrahydro-1H-[1,2,4]triazino[4′,3′:4,5][1,4]oxazino[2,3-f]indol-2(3H)-one 2,2,2-trifluoroacetate (0.65 g, crude). Prep-HPLC (Table 3, Method 29) purification of 20 mg of crude product gave 1-methyl-10-(3-methyl-azetidin-3-yl)-3,5,9,10-tetrahydro-8H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one 2,2,2-trifluoroacetate (0.011 g). 1H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H), 9.15 (s, 1H), 8.91 (brs, 1H), 6.80 (s, 1H), 5.95 (s, 1H), 4.98 (m, 1H), 4.45 (s, 2H), 4.11 (m, 4H), 3.25 (m, 1H), 2.84 (m, 2H), 1.40 (s, 3H), 1.20 (m, 3H). LC/MS (Table 1, Method 4) Rt=0.799 min; MS m/z: 328 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([OH:24])=[CH:22][C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42].C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:30].[CH2:1]([N:8]1[CH2:13][C:12]2[C:14]3[C:23]([O:24][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH:32]4[CH3:31])=[CH:22][C:21]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][C:15]=3[O:16][C:17]([CH3:19])([CH3:18])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1
Reactant: CC1CCCCN1CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCCCC2C)c2c(c1)OC(C)(C)C1=C2CN(Cc2ccccc2)CC1

Procedure:
2-Benzyl-5,5-dimethyl-10-hydroxy-8-(1-pentyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, γ-(2-methylpiperidino)- butyric acid hydrochloride and dicyclohexylcarbodiimide in equimolar amounts are reacted as in Example 1 to give the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.CO[C:14]1[CH:15]=[C:16]2[C:21](=[C:22](O)[CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2.[C:25](O)(=O)[C:26](O)=O>CN(C=O)C>[CH:21]1[C:22]2[C:23](=[CH:11][CH:2]=[CH:3][CH:4]=2)[CH:14]=[CH:15][C:16]=1[CH:17]1[CH2:8][CH:7]2[N:20]([CH2:25][CH2:26][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]4[C:11]=3[N:10]=[CH:9][CH:8]=[CH:7]4)[CH:19]([CH2:5][CH2:6]2)[CH2:18]1
Reactant: COc1cc(O)c2ncccc2c1
Reactant: Oc1cccc2cccnc12
Reactant: O=C(O)C(=O)O
Solvent: CN(C)C=O
Product: c1ccc2cc(C3CC4CCC(C3)N4CCOc3cccc4cccnc34)ccc2c1

Procedure:
The title compound is prepared according to Example 8, Step 5, except 8-hydroxyquinoline is used in place 6-methoxyquinolin-8-ol. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. oxalic acid in DMF to precipitate a white solid. Yield: 51%; mp: 110-113° C.; MS (ES) m/z: 409 (MH)+.
Reaction SMILES: [C@@H]1(C2C=C3C(C=C(C(O)=O)C(=O)O3)=CC=2)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1[OH:3].ON1C(=O)CCC1=O.[CH:34]1([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C=O>[C:41]([NH:40][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:3]
Reactant: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.68 g (0.01 mol) of 7-β-galactosylcoumarin-3-carboxylic acid, supra, 2.30 g (0.02 mol) of N-hydroxy-succinimide, and 2.27 g (0.011 mol) of dicyclohexylcarbodiimide in 25 ml of dimethylformamide (DMF) was stirred under argon at room temperature for 1 hour. A thick precipitate of dicyclohexylurea formed and was removed by filtration. The clear filtrate was combined with 2.52 grams (g) of the hydrochloride salt of N-(tert-butyloxycarbonyl)-1,6-hexanediamine [Stahl et al, J. Org. Chem. 43:2285(1976)]. The solution was cooled to 0° C. and 2.8 ml (2.02 g, 0.02 mol) of triethylamine was added. The reaction was allowed to stir at room temperature for 2 hours, then filtered to remove the precipitate of triethylamine hydrochloride. Evaporation of the DMF under reduced pressure gave an oily residue that was stirred for 15 minutes with 100 ml of 2 N hydrochloric acid. The heavy precipitate that formed was filtered, washed with water, and dried.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]([C:20]2[C:25]([O:26][CH3:27])=[N:24][C:23]([CH3:28])=[CH:22][N:21]=2)[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:27][O:26][C:25]1[C:20]([N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[S:8]([C:7]2[C:2]([C:34]3[CH:35]=[CH:36][C:31]([S:30][CH3:29])=[CH:32][CH:33]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[N:21][CH:22]=[C:23]([CH3:28])[N:24]=1
Reactant: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1Cl
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1-c1ccc(SC)cc1

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.022 g) was added to a deoxygenated mixture of 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.405 g), 4-methylthiophenylboronic acid (obtained by the procedure described in Tetrahedron Lett., 1993, 34, 8237) (0.148 g), toluene (4.5 ml), ethanol (2.5 ml) and 2M sodium carbonate solution (7 ml) and the mixture was stirred and heated under reflux for 18 hours. Water was added and the mixture was extracted three times with ethyl acetate. The organic extracts were combined, washed with saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-35% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-methylthiophenyl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.415 g) as an oil; 1H NMR (CDCl3): 0.0 (s, 9H), 0.8 (t, 2H), 2.5 (s, 3H), 2.55 (s, 3H), 3.6 (t, 2H), 3.9 (s, 3H), 4.8 (s, 2H), 7.3-7.5 (m, 3H), 7.6-7.7 (m, 2H), 7.8 (s, 1H), 8.7 (dd, 1H), 8.8 (dd, 1H); mass spectrum (+ve ESP): 533 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:28]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:29]([C:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][C:50](=[O:52])[NH2:51])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:28]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:29]([C:45]([NH:47][C@H:48]([C:53]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:54])[CH2:49][C:50](=[O:52])[NH2:51])=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Yield: 28.4 %

Procedure:
compound SP323C2. Same procedure as above with Trp-NH(CH2)4NHBoc (108.7 mg, 0.29 mmol), N-Boc-Tyr(Bn)-Asn-OH (140.9 mg, 0.29 mmol), EDC (61.8 mg, 0.32 mmol) and HOBt (43.6 mg, 0.32 mmol) in CH2Cl2/DMF (2 mL, 1/1). The crude residue was purified by flash column chromatography on silica gel (2-6% MeOH/CH2Cl2) to give an white solid (69.3 mg, 28%). 1H NMR (300 MHz, DMSO-d6) δ 1.18-1.37 (m, 4H, 2 CH2 putrescine), 1.28 (s, 9H, (CH3)3), 1.37 (s, 9H, (CH3)3), 2.42-3.2 (m, 10H, CH2 Tyr, CH2 Trp, CH2 Asn, 2 CH2 putrescine), 4.1 (m, 1H, CHα), 4.36 (m, 1H, CHα), 4.53 (m, 1H, CHα), 5.03 (s, 2H, CH2 (Bn)), 6.71 (m, 1H), 6.8-7.53 (m, 17H), 7.84 (m, 1H), 8.01 (d, J=9 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 10.73 (s, 1H). 13C NMR (75 MHz, DMSO-d6) δ 26.4, 27 (2 CH2 putrescine), 27.4 (CH2 Trp), 28.4 ((CH3)3), 36.6, 37.2 (CH2 Tyr, CH2 Asn), 38.4, 39.4 (2 CH2 putrescine), 49.8, 54, 55.9 (CHα Tyr, Asn, Trp), 69.2 (CH2 (Bn)), 77.5, 78.2 (C(CH3)3), 110.2, 111.3, 114.4, 118.3, 120.9, 123.6, 127.4, 127.7, 127.9, 128.5, 130.3, 130.4, 136.1, 137.4 (19 aromatic C), 155.4, 155.7, 157 (Car-O, 2 CO carbamate), 170.7, 170.9, 171.8, 172.1 (4 CO amide). Anal. Calcd. for C45H59N7O9: C, 64.19; H, 7.06; N, 11.64. Found: C, 63.97; H, 7.05; N, 11.76.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4](C)[C:5](=O)OC(C)(C)C.N1C=CC=CC=1.[C:19]([Cl:24])(=[O:23])[O:20][CH2:21][CH3:22]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[ClH:24].[C:19](=[O:23])([O:1][CH2:2][CH2:3][NH:4][CH3:5])[O:20][CH2:21][CH3:22]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCNC
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Synthetic Example 1 and ethyl acetate (20 mL) were added pyridine (0.97 mL) and 4 -dimethylaminopyridine (catalytic amount), and ethyl chlorocarbonate (1.25 mL) was added. After stirring overnight at room temperature, ethyl acetate (50 mL) was added to the reaction solution, and washed sequentially with water (50 mL), 5% aqueous solution of citric acid (50 mL), and saturated saline (50 mL), followed by drying over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and to the residue was added 4N hydrogen chloride-ethyl acetate solution (10 mL). After stirring at room temperature for 2 hrs, diethyl ether (10 mL) was added thereto, and the depositting solid was collected by filtration. The solid was dried under reduced pressure to give title compound as white solid (1.66 g).
Reaction SMILES: [NH2:1][C:2]1[N:27]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>O1CCCC1.O>[CH:35]1([C:38]([NH:1][C:2]2[N:27]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)n(C)n1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C)n1
Yield: 80.6 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (117 mg, 0.322 mmol) and triethylamine (134 μL, 0.966 mmol) in tetrahydrofuran (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (38.0 μL, 0.419 mmol), and the mixture was stirred at room temperature for 12 hr. Cyclopropanecarbonyl chloride (29.3 μL, 0.322 mmol) was further added and the mixture was stirred for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, sodium carbonate (100 mg), methanol (2 mL) and water (100 μL) were added to the residue, and the mixture was stirred at 50° C. for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, ethyl acetate) and recrystallized from ethyl acetate to give the title compound (112 mg, 60%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:27])[CH2:4][N:5]1[C:9]([C:10]2[N:11]=[C:12]3[N:22]([CH:23]=2)[CH2:21][CH2:20][O:19][C:18]2[C:13]3=[CH:14][CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=2)=[N:8][CH:7]=[N:6]1.[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:25]/[C:24]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:22]([CH:23]=[C:10]([C:9]3[N:5]([CH2:4][CH:3]([O:2][CH3:1])[CH3:27])[N:6]=[CH:7][N:8]=3)[N:11]=1)[CH2:21][CH2:20][O:19]2)=[O:26]
Reactant: COC(C)Cn1ncnc1-c1cn2c(n1)-c1ccc(C(C)=O)cc1OCC2
Reactant: COC(OC)N(C)C
Product: COC(C)Cn1ncnc1-c1cn2c(n1)-c1ccc(C(=O)/C=C/N(C)C)cc1OCC2
Temperature: 130 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
A mixture of 1-{4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (163 mg, 0.44 mmol) and DMF-DMA (112 mg, 0.88 mmol) in xylenes (10 mL) was stirred at 130° C. for 48 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to afford (2E)-3-(dimethylamino)-1-{4-[1-(2-methoxypropyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (120 mg, 90% yield). LCMS (ESI) m/z: 422.1 [M+H+].
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:11]([NH2:17])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH2:1]([NH:8][C:9]([NH:17][CH2:11][C:12]1[O:16][CH:15]=[CH:14][CH:13]=1)=[S:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCc1ccco1
Reactant: CCCCCCCN=C=S
Solvent: c1ccccc1
Product: CCCCCCCNC(=S)NCc1ccco1

Procedure:
To a mixture of 3.1 grams (0.02 mole) of n-heptyl isothiocyanate and 25 milliliters of benzene was added 1.77 milliliters (0.02 mole) of furfuryl amine. The mixture was refluxed for 30 minutes on a steam bath and then evaporated under vacuum to yield 1-n-heptyl-3-furfuryl thiourea. The product was cooled and 4.1 grams (0.02 mole) of bromoethylamine hydrobromide and 25 milliliters of ethanol 2B was added. The resulting mixture was refluxed on a steam bath overnight. The solid product was removed by filtration and air dried. A yield of 5.2 grams of solid, melting point 140°-145° C., was obtained. Structure of the product was confirmed by NMR.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH2:17])=[CH:12][CH:11]=1.[Cl:27][C:28]1[C:29]([Cl:41])=[C:30]([Cl:40])[C:31]([Cl:39])=[C:32]2[C:37](=O)[O:36][C:34](=[O:35])[C:33]=12.[OH-].[Na+]>O>[CH3:25][N:24]([CH3:26])[C:21]1[CH:20]=[CH:19][C:18]([C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=2)=[CH:17][C:37]2([CH:17]=[C:16]([C:13]3[CH:14]=[CH:6][C:5]([O:4][CH3:1])=[CH:11][CH:12]=3)[C:18]3[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:32]3[C:33](=[C:28]([Cl:27])[C:29]([Cl:41])=[C:30]([Cl:40])[C:31]=3[Cl:39])[C:34](=[O:35])[O:36]2)=[CH:23][CH:22]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: C=C(c1ccc(OC)cc1)c1ccc(N(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(=CC2(C=C(c3ccc(OC)cc3)c3ccc(N(C)C)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccc(N(C)C)cc2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Into 25 ml of acetic anhydride, 13.0 g of 1-(p-methoxyphenyl)-1-(p-dimethylaminophenyl)ethylene and 9.3 g of tetrachlorophthalic anhydride were added and the mixture was stirred for 2 hours at 120° C. After adding the reaction mixture into 200 ml of water and making the mixture alkaline with sodium hydroxide, the alkaline mixture was extracted with 70 ml of toluene. The solid matter obtained by distilling off toluene from the extract was recrystallized from butanol while purifying with activated carbon to obtain 14.3 g of pale yellow crystals melting at 133°-135° C.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: CONC(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a stirred solution of trans O-Methyl-N-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]ethyl}-hydroxylamine (0.25 g; 0.83 mmol) prepared as described in example P17 and triethylamine (0.15 mL; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.16 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.32 g (84% of theory) of trans 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethyl}-amide as white solid (m.p. 110° C.-113° C.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1(=[CH:12][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: Cc1ccccc1
Product: C(=C1CCCCC1)N1CCCC1
Reaction time: 12 h

Procedure:
Cyclohexanecarboxyaldehyde (23.2 g) and pyrrolidine (14.5 g) were dissolved in toluene (200 ml), and the mixture was heated under reflux using a Dean-Stark distillation apparatus. After 12 hours, the solvent was removed. The residue was distilled under reduced pressure (60° C., 1 mmHg) to give 22.6 g of 1-(cyclohexylidene-methyl)pyrrolidine.
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.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(F)c1
Product: Fc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-fluorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 21 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[CH:8][CH:7]=[C:6]2Br.C([Li])(C)(C)C.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([OH:32])([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc2cccc(Br)c2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCN(Cc4ccccc4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A solution of 5.0 gm (21.1 mMol) 6-methoxy-4-bromonaphthalene in 120 mL tetrahydrofuran was first cooled to −78° C. and then 27.3 mL (46.4 mMol) tert-butyllithium (1.7 M in pentane) were added and the resulting solution stirred for about 1.5 hours. At this point a solution of 4.1 mL (22.1 mMol) 1-benzylpiperidin-4-one in 30 mL tetrahydrofuran was added and the reaction mixture was allowed to warm gradually to room temperature. After 3 hours the reaction was quenched by the addition of 2 N sodium hydroxide. The resulting mixture was extracted with diethyl ether. The organic extracts were combined, washed with saturated aqueous sodium chloride, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 0 to 2% methanol. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to provide 4.62 gm (63%) of the desired compound as a white solid.