Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][N:5]2[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C@@H:4]2[CH2:3]1.Br[C:21]1[CH:26]=[N:25][C:24]([CH:27]2[CH2:29][CH2:28]2)=[CH:23][N:22]=1.CC(C)([O-])C.[K+]>O1CCCC1.ClCCl>[CH:27]1([C:24]2[N:25]=[CH:26][C:21]([O:1][C@@H:2]3[CH2:19][N:5]4[C:6](=[O:18])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:10][C@@H:4]4[CH2:3]3)=[N:22][CH:23]=2)[CH2:29][CH2:28]1
Reactant: Brc1cnc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.6 %

Procedure:
To tert-butyl (8S,9aS)-8-hydroxy-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (270 mg, 1 mmol, Part B) and 2-bromo-5-cyclopropylpyrazine (299 mg, 1.5 mmol) in tetrahydrofuran (3 mL) and dichloromethane (1 mL) was added potassium t-butoxide (3 mL, 3 mmol, 1 M in tetrahydrofuran). The mixture was stirred at room temperature for three days, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate) to give 255 mg (65.6% yield) of the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (m, 4H), 1.47 (s, 9H), 2.01 (m, 2H), 2.61 (m, 3H), 3.01 (m, 2H), 3.80-3.98 (m, 3H), 4.22 (m, 2H), 5.40 (m, 1H), 7.95 (d, J=1 Hz, 1H), 8.02 (d, J=1 Hz, 1H); MS (ESI) m/z 389.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])[C:23](=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH:18][C:37]([NH:36][C:22]2[CH:21]=[C:20]([Cl:19])[CH:35]=[CH:34][C:23]=2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:38])(=[O:16])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)ccc1O
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)ccc1O
Yield: 93.1 %

Procedure:
320 mg (1.17 mmol) of 3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide and 447 mg (1.17 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 611 mg (yield 93%) of benzyl 2-{[(3-t-butoxycarbonyl-4-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDC13): 1.62 (9H, s), 5.35 (2H, s), 7.01-7.05 (2H, m), 7.37-7.41 (5H, m), 7.96 (1H, d), 8.10 (1H, dd), 8.46-8.48 (2H, m), 10.99 (1H, s), 11.66 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14].C(O)(=O)C.S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1c(F)cc([N+](=O)[O-])cc1F
Yield: 96.7 %

Procedure:
A solution of the obtained diethyl 2,6-difluoro-4-nitrophenylmalonate (42 g) in a mixed solvent of acetic acid (200 mL), water (150 mL) and conc. sulfuric acid (50 mL) was heated under reflux for 18 hr, and the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate (×2). The organic layer was back-extracted with 10% sodium carbonate aqueous solution, and the aqueous layer was acidified with 2N hydrochloric acid. The precipitate was collected by filtration to give 2-(2,6-difluoro-4-nitrophenyl)acetic acid (27.90 g, 128 mmol, 92.0%) as white crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[N:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1.CO>CC#N>[F:40][C:37]([F:38])([F:39])[C:34]1[N:33]=[N:32][C:31]([CH2:30][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[N:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:4][CH2:3]2)=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccc(CBr)nn1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=c1ccc2ncc(=O)n3c2n1CC3CN1CCC(NCc2ccc(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a synthesis see Example 2(j)) (56.3 mg, 0.187 mmol), K2CO3 (34.4 mg, 0.249 mmol) and 3-(bromomethyl)-6-(trifluoromethyl)pyridazine (for a synthesis see Preparation 1 below) (30 mg, 0.124 mmol) in CH3CN (1 ml) and MeOH (0.1 ml) was stirred at room temperature overnight. LCMS showed amine derivative remaining. An excess of 3-(bromomethyl)-6-(trifluoromethyl)pyridazine (25 mg) was added. The mixture was stirred at room temperature for 1 h. The solid was filtered off and the solvent evaporated. Purification by flash chromatography using Flashmaster II and mixtures of DCM and MeOH as eluent afforded 2-{[4-({[6-(trifluoromethyl)-3-pyridazinyl]methyl}amino)-1-piperidinyl]methyl}-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (17 mg, 30%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N+:17]([O-])=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si]([C:34]#[N:35])(C)C.CN(C)C(Cl)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:34]#[N:35])[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(CCCc1cc[n+]([O-])cc1)CO[Si](C)(C)C(C)(C)C
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC(CCCc1ccnc(C#N)c1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of the crude 4-[5-(tert-butyldimethylsilanyloxy)-4-(tert-butyldimethylsilanyloxy-methyl)-pentyl]pyridine 1-oxide (0.43 g) prepared in (5) in chloroform (5 mL) were added trimethylsilyl cyanide (0.17 mL) and N,N-dimethylcarbamoyl chloride (0.12 mL). The reaction mixture was stirred at RT for 12 hr. Saturated aqueous NaHCO3 was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=9/1) to give the title compound (0.40 g, 87%).
Reaction SMILES: [NH2:1][C@@H:2](/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:21]#[C:22]Br.N>CO>[N+:13]([C:10]1[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C@H:2]2[CH2:3][O:4][C:22]([NH2:21])=[N:1]2)=[CH:8][CH:9]=1)([O-:15])=[O:14]
Reactant: N#CBr
Reactant: N[C@@H](/C=C/c1ccc([N+](=O)[O-])cc1)CO
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=N[C@@H](/C=C/c2ccc([N+](=O)[O-])cc2)CO1
Reaction time: 48 h
Yield: 33.9 %

Procedure:
To a solution of (E)-(S)-2-amino-4-(4-nitro-phenyl)-but-3-en-1-ol (2.5 g) in methanol (90 ml) at room temperature was added sodium acetate (3.0 g) followed by a solution of cyanogen bromide (1.65 g) in methanol (10 ml) dropwise over 15 minutes. The reaction mixture was stirred for 2 days, then 25% aqueous ammonia (8.2 ml) was added and the solution stirred for 1 hour at room temperature. The solvent was evaporated in vacuo and the residue purified by Isco chromatography (column: Silicycle Si-Amine, AcOEt) to give (S)-4-[(E)-2-(4-nitro-phenyl)-vinyl]-4,5-dihydro-oxazol-2-ylamine (950 mg) as a yellow oil. MS (ISP): 234.1 ([M+H]+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[N+:37]=[N-:38])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
The bis(4-acetyloxyphenylsulfonyl)methane in Synthesis Example 3, 4.5 g (0.011 mol), was dispersed in 49 g of dichloromethane. To the dispersion was added 2.5 g (0.016 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring at room temperature, 3.0 g (0.015 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) was added to the dispersion, and after 5 minutes, 50 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 50 g of water. The organic layer was concentrated and 8 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 10 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 1.5 g (yield 31%) of fine yellow crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.CC1C=CC(N=C=S)=CC=1>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][C:6]([CH3:37])=[CH:7][CH:2]=4)=[S:35])=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)[C:23]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: Cc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(C)cc4)cc3)cc2C1=O

Procedure:
The compound of example 53 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 4-methyl phenyl isothiocyanate. The compound of example 53 was used directly without isolation for the preparation of compound of example 54.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37].CCCCCC>C(OCC)(=O)C>[ClH:37].[CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1nc(CC2CCNCC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
tert-Butyl 5-(benzyloxy)-2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate (4.4 g, 8.8 mmol) was dissolved in ethyl acetate (44 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 68 mL, 270 mmol) was added, followed by stirring at room temperature for 3 hours. Hexane (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, whereby a solid was deposited. The resulting solid was collected by filtration, and dried under reduced pressure to afford the title compound (3.7 g, 8.5 mmol) as a white solid (yield 95%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12]([OH:14])=O)=[CH:7][CH:6]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:48][N:49]([CH3:60])[CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:12](=[O:14])/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:55][CH:54]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Method A; To a mixture of 3 (2.50 g, 8.00 mmol), EDC.HCl (1.84 g, 9.60 mmol) and HOBt (1.30 g, 9.62 mmol) in DMF (50 ml) was added a solution of 4-(2-(dimethylamino)ethoxy)benzene-amine dihydrochloride (2.23 g, 8.81 mmol) and N,N-Diisopropylethylamine (4.13 g, 32.0 mmol) under ice cooling, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with AcOEt, the organic layer was washed with H2O×2, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: AcOEt then CHCl3/MeOH, 10:1) and recystallization from AcOEt-hexanes gave 4 (43%). 4: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.4), 2.33 (6H, s), 2.71 (2H, t, J=5.7 Hz), 2.77 (2H, q, J=7.4 Hz), 3.43 (3H, s), 4.04 (2H, t, J=5.7 Hz), 5.09 (2H, s), 6.78 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=9.0 Hz), 7.00 (2H, d, J=8.8 Hz), 7.00 (1H, brs) 7.06 (2H, m), 7.12-7.23 (3H, m), 7.41 (2H, d, J=9.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[N+:12]([O-])([O-:14])=[O:13].[K+].O>OS(O)(=O)=O>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: Cc1cc(F)cc(C(=O)O)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1cc(F)cc(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Fluoro-5-methylbenzoic acid (4 g, 25.96 mmol) and KNO3 (2.884 g, 28.556 mmol) were dissolved in conc. H2SO4 (32 mL) at 0° C. The mixture was stirred at rt for 1 h. Water (60 mL) was added, and the resulting precipitate was filtered and dried to provide the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1([C:22]([NH2:24])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[CH:25](OCC)(OCC)OCC>>[CH2:15]([N:12]1[CH2:11][CH2:10][C:9]2([N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH:25]=[N:24][C:22]2=[O:23])[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1NC1(C(N)=O)CCN(Cc2ccccc2)CC1
Reactant: CCOC(OCC)OCC
Product: Cc1ccccc1N1C=NC(=O)C12CCN(Cc1ccccc1)CC2
Temperature: 150 °C
Reaction time: 240 h

Procedure:
4-(2-methyl-phenyl-amino)-1-(phenylmethyl)-4-piperidine-carboxamide (10.35 g) was dissolved in 60 ml triethyl orthoformate and stirred at 150° C. for 10 d. After cooling to 0° C, the reaction mixture was evaporated and the resulting brown oil was chromatographed on silica gel using dichloromethane:methanol 19:1 as eluent. 8-benzyl-1-(2-methyl-phenyl)-1,3,8-triazaspiro[4,5]dec-2-en-4-one (4.71 g) was obtained as a brown foam. MS: m/z=334 (M+H)+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[CH:21].C1COCC1>[Cu]I.CCOCC>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Ic1ccc(N2CCCC2)cc1
Reactant: C#CCOCCCCBr
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: BrCCCCOCC#Cc1ccc(N2CCCC2)cc1
Yield: 10.7 %

Procedure:
A mixture of 1-(4-iodophenyl)pyrrolidine (22.8 g), the product of stage (i) (16.0 g), BTPC (1.5 g) and copper (I) iodide (150 mg) in DEA (125 ml) and THF (125 ml) was stirred under nitrogen for 18 h. The dark mixture was treated with ether (250 ml), the precipitate was removed by filtration and the filtrate was concentrated to a black oil which was purified by FCC (hexane→System D 9:1) to give the title compound as a pale yellow oil (3.0 g) T.l.c. (System D 9:1) Rf 0.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:44]1[CH2:49][CH2:48][N:47]([C:50]2[N:55]=[CH:54][C:53]([CH2:56]O)=[CH:52][CH:51]=2)[CH2:46][CH2:45]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:56][C:53]4[CH:54]=[N:55][C:50]([N:47]5[CH2:48][CH2:49][O:44][CH2:45][CH2:46]5)=[CH:51][CH:52]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: OCc1ccc(N2CCOCC2)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(N3CCOCC3)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 27.5 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (6-morpholinopyridin-3-yl)methanol (29 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, 7,8-bis(4-chlorophenyl)-2-((6-morpholinopyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20.5 mg, 11%) was obtained as yellow powder. MS M+H=533; 1H NMR (CDCl3) 8.26 δ (1H, d, J=5.0 Hz), 8.15 (1H, s), 7.65 (1H, d, J=5.0 Hz), 7.25-7.36 (6H, m), 7.09 (2H, d, J=10.0 Hz), 6.60 (1H, d, J=10.0 Hz), 5.10 (2H, s), 3.80 (4H, t, J=5.0 Hz), 3.50 (4H, t, J=5.0 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.CI.[C:15](=O)([O-])O.[K+]>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:10]([O:12][CH3:15])=[O:11])[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)C1(c2cccs2)CCC1
Reactant: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cccs2)CCC1

Procedure:
1-(2-Thienyl)cyclobutanecarboxylic acid, methyl iodide, and potassium hydrogen carbonate were reacted in DMF at room temperature to obtain methyl 1-(2-thienyl)cyclobutanecarboxylate.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:21]1[CH:20]=[CH:19][C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Brc1ncccn1
Product: COc1ccc(F)cc1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound was prepared by method C using compound 12b and 2-bromopyrimidine. HRMS (ESI+): m/z=375.1249 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Br:12])=[O:11].[Br:13]Br>CCCCCC>[Br:13][CH:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[C:10]([Br:12])=[O:11]
Reactant: BrBr
Reactant: O=C(Br)Cc1c(Cl)cccc1Cl
Solvent: CCCCCC
Product: O=C(Br)C(Br)c1c(Cl)cccc1Cl

Procedure:
To 36.0 g (0.134 mols) 2,6-dichlorophenyl acetyl bromide, are added in drops at 160 degrees C., 21.5 g (0.134 mols) bromine over 3 hours, and the resultant mixture is then stirred for another 2 hours at 170 degrees C. While stirring, 100 ml hexane are added at 90 degrees C., followed by suction-filtering of the bromide after cooling.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH2:30][Cl:31].CN(C=O)C>CC(C)=O>[Cl:31][CH2:30][CH2:29][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(-c2ccc(O)cc2)c2sccc2c1=O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)n1nc(-c2ccc(OCCCCl)cc2)c2sccc2c1=O
Yield: 98 %

Procedure:
A solution of the product of step 3 (858 mg, 3 mmol), K2CO3 (1.24 g, 3.0 eq.), and 3-bromo-1-chloropropane (0.3 mL, 1.05 eq.) in acetone:DMF (25 mL:3 mL) was heated to 80° C. overnight. The mixture was then filtered, washed with acetone, and concentrated to dryness to afford the product of step 4 (1.17 mg, 98% yield): Mp 92-4° C.; MS m/z 363 (M+H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:20]1([C:19](=[O:26])[CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
Lithium diisopropyl amide (16.9 mL, 1.5 M in cyclohexane, 25.4 mmol) was added to THF (40 mL) at −78° C. A solution of 4-picoline (2.50 mL, 25.4 mmol) in THF (30.0 mL) was added dropwise to the LDA solution. The dry ice bath was removed. The reaction mixture was stirred at 0° C. for 30 minutes, and cooled down to −78° C. A solution of N-methoxy-N-methylbenzamide (1) (5.00 g, 29.6 mmol) in THF (20.0 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water, and extracted with ethyl acetate (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered, and the solvent was removed under vacuum to give the crude product. The crude material was triturated with hot hexane, and filtered to give 1-phenyl-2-(pyridin-4-yl) ethanone (2) as a yellow solid (3.53 g, 17.9 mmol, 70% yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][CH2:27][CH3:28]>>[CH3:24][N:25]([CH2:26][CH2:27][CH3:28])[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:23])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CCCNC
Product: CCCN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylpropylamine using a similar procedure to that described for Example 2, product further purified by mass directed auto-prep.