Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C:12](=[CH:13][C@H:14]([OH:31])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:50]O)(C)(C)C>C1(C)C=CC=CC=1>[CH2:39]([Si:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:12]3([O:50][C@@H:13]3[C@H:14]([OH:31])[C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[C@@H:17]3[CH2:30][C@@H:18]3[C:19]2=[O:29])[CH2:11]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OO
Reactant: C[C@]12CC[C@H](O[Si](Cc3ccccc3)(Cc3ccccc3)Cc3ccccc3)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@H]3[C@@H]([C@@H](O)[C@H]4O[C@]45C[C@@H](O[Si](Cc4ccccc4)(Cc4ccccc4)Cc4ccccc4)CC[C@]35C)[C@@H]1[C@@H]1C[C@@H]1C2=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
24 g of 3β-tribenzylsilyloxy-7β-hydroxy-15β,16β-methylene-5-androsten-17-one is dissolved in 50 ml of toluene, combined with 500 mg of vanadium(IV) oxide acetylacetonate, and heated to 80° C. A solution of 75 ml tert.-butyl hydroperoxide (10 ml 80% tert.-butyl hydroperoxide in 100 ml of toluene) is added dropwise to the reaction mixture, and the latter is allowed to stand for 1.5 hours at this temperature. After cooling, the mixture is washed with water and saturated sodium chloride solution, dried, and evaporated under vacuum, thus obtaining 24.5 g of 3β-tribenzylsilyloxy-5,6β-epoxy-7β-hydroxy-15β,16β-methylene-5β-androstan-17-one.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[Cl:34][C:35]1C=CC(CN)=CC=1>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]3[CH:33]=[CH:32][C:35]([Cl:34])=[CH:31][CH:30]=3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: NCc1ccc(Cl)cc1
Reactant: Nc1nc(-n2cc(C(=O)NCC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(-n2cc(C(=O)NCc3ccc(Cl)cc3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Compound 22 was prepared in a manner similar to that of compound 21 using 4-chlorobenzylamine instead of cyclopentylamine, MS 501.19 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[CH2:9][CH2:10][C:11]([NH:13][O:14]C2CCCCO2)=[O:12])=[CH:4][C:3]=1[CH3:23].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:21][CH3:22])[CH2:9][CH2:10][C:11]([NH:13][OH:14])=[O:12])=[CH:4][C:3]=1[CH3:23]
Reactant: COC(CCC(=O)NOC1CCCCO1)c1ccc(F)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H](CCC(=O)NO)c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To the solution of 4R)-4-(4-fluoro-3-methylphenyl)-4-methoxy-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (66 mg, 0.2 mmol) in 4 mL DCM was slowly added 2 mL TFA and the resulting solution stirred for 30 min at 25° C. The solvent was evaporated and the product isolated by flash column chromatography eluting with 0% to 10% methanol/DCM gradient solvent to give 32 mg of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:11]3)[C:4](=[O:24])[CH:3]=1.[H-].[Na+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C1COCC1>[N:19]1([CH2:18][CH2:17][N:13]2[C:14]3[C:10](=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:33][C:32]5[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=5)=[CH:3][C:4]4=[O:24])=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=c1cc(O)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 65 °C
Yield: 13.5 %

Procedure:
To a solution of 4-hydroxy-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-one (100 mg, 0.308 mmol) in THF was added NaH (25 mg, 0.62 mmol) followed by 4-(trifluoromethyl)benzyl bromide (88 mg, 0.37 mmol). After heating at 65° C. overnight, the reaction mixture was cooled down, filtered through a thin layer of Celite, washed with CH2Cl2, and the filtrate was concentrated. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 90:10) gave 1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)benzyloxy)pyridine-2(1H)-one (20 mg, 13%) as a white solid. According to the procedure of Example 1, the HCl salt was made to give the title compound as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.12 (m, 1H), 7.80-7.67 (m, 6H), 7.62 (d, J=7.5 Hz, 1H), 7.34 (m, 1H), 6.13 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.27 (s, 2H), 4.58-4.54 (m, 2H), 2.89 (m, 2H), 2.52-2.42 (m, 4H), 1.73-1.64 (m, 4H); ESI MS m/z 483 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:48][O:49][C:50]1[CH:51]=[C:52]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1>CN(C=O)C>[CH3:48][O:49][C:50]1[CH:51]=[C:52]([N:58]2[CH2:59][CH2:60][N:61]([C:11]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[O:13])[CH2:62][CH2:63]2)[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(OC)cc(N2CCN(C(=O)c3ccnc4ccccc34)CC2)c1

Procedure:
2 g (11.5 mmol) of quinoline-4-carboxylic acid were suspended in 80 ml of DMF. With stirring, 1.74 g (17.2 mmol) of N-methylmorpholine and then a solution of 8.95 g (17.2 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 2.56 g (11.5 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 25 ml of DMF were added to this mixture. The mixture was stirred at RT for 12 h, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(C(=O)O)ccc43)ncn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(C(=O)O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 19b (65 mg, 0.37 mmol) in 1.5 mL of DCM, was added TFA (1.5 mL, 19.5 mmol) and the reaction was stirred at room temperature for 2 h. The mixture was concentrated to give 19c.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:13]1COCC1>>[CH:11]([CH:8]1[CH2:7][CH2:6][C:5]2([O:1][CH2:2][CH2:3][O:4]2)[CH2:10][CH2:9]1)=[CH2:13]
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: C1CCOC1
Product: C=CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask containing triphenylphosphonium bromide-sodamide complex (20.04 g, 48.10 mmol) was added THF (100 mL). After stirring @ rt for 1 hour, the solution was bright yellow (with some ppt). The r×n mixture was cooled to 0° C. and a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (693 mg, 4.07 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) in THF (20 mL) was added dropwise via syringe. After the complete addition, the reaction mixture turned light peach and was stirred, warming to rt overnight. The reaction was quenched cautiously with saturated aq NaHCO3 at 0° C. and allowed to warm to room temperature, followed by water and extraction with ether. The concentrated organic layers were purified by flash chrom (silica gel, ether, stains PAA). To avoid losing some material on the rotovap (seems volatile), the bath temperature was kept under 35° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCCCCCCBr
Reactant: COc1cc(NS(=O)(=O)c2ccc(C)cc2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCN(c1cc(OC)cc(OC)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: 120 °C
Yield: 96.3 %

Procedure:
A mixture of N-(3,5-Dimethoxy-phenyl)-4-methyl-benzenesulfonamide (15.0 g, 48.9 mmol), 1-bromoheptane (9.63 g, 53.8 mmol) and potassium carbonate (17.1 g, 124.2 mmol) in anhydrous DMF (100 mL) was stirred and heated at 120 ° C. for 4 h, and then cooled to room temperature and poured into ice-cold water (400 mL). Diethyl ether (400 mL) was added to extract the product. The ethereal solution was separated and washed with water, brine and dried with Na2SO4. Removal of solvent and drying reagent provided 19.50 g of light yellow liquid, which was treated with small amount of diethyl ether to give 19.10 g (96.4%) of the title compound as a white solid upon cooling.
Reaction SMILES: [CH2:1]1C2NC(=CC=2)CC2NC(=CC=2)CC2NC(=CC=2)CC2NC1=CC=2.[C:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])[CH3:26].Cl>CO>[CH3:1][O:32][C:31](=[O:33])[CH2:30][CH2:29][CH2:28][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)CCCC(=O)O
Reactant: c1cc2[nH]c1Cc1ccc([nH]1)Cc1ccc([nH]1)Cc1ccc([nH]1)C2
Agent: Cl
Solvent: CO
Product: COC(=O)CCCC(C)=O
Yield: 84 %

Procedure:
Calix[4]pyrrole meso-monoester 3. 4-Acetylbutyric acid (3.8 g, 29 mmol) was dissolved in methanol (50 mL) in a 100 mL round bottomed flask with magnetic stirring. Concentrated hydrochloric acid (1 mL, 37%) was added and the mixture heated at reflux for 12 hr. The solvent was then removed in vacuo and the residue redissolved in dichloromethane (50 mL). The solution was then washed with saturated NaHCO3 (aq) solution (2×50 mL) and then brine (1×100 mL). The organic layer was separated and then dried over MgSO4 and reduced in vacuo to give the methyl ester, methyl-4-acetylbutyrate, as a yellow oil (3.5 g, 24.3 mmol) corresponding to a yield of 84%. 1H NMR (CDCl3) 3.64 (s, 3, OCH3), 2.49 (t, J=7.2 Hz, 2, CH2), 2.32 (t, J=7.2 Hz, 2, CH2), 2.12 (s, 3, CH3), 1.86 (m, 2, CH2). 13C NMR (CDCl3) 207.0, 172.8, 50.7, 41.7, 32.3, 29.1, 18.25. CI MS m/z @ 145 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][F:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>C(Cl)Cl>[F:9][CH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([NH:10][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[N:5]=1
Reactant: Cc1cc(CF)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(CF)n1
Reaction time: 16 h
Yield: 52.3 %

Procedure:
To a stirring solution of 4-methyl-6-fluoromethyl-2-pyrimidinamine (1.4 mmol) in 25 ml of CH2Cl2 was added o-carbomethoxybenzenesulfonyl isocyanate (1.77 mmol). After stirring 16 hours the reaction was concentrated and the resulting solid washed with butyl chloride to afford 0.28 g of the desired product, m.p. 181°-186° C. NMR (90 MHz, CDCl3): δ 2.5 (s, 3H); 4.0 (s, 3H); 5.2 (s, 1H); 5.7 (s, 1H); 7.0 (s, 1H); 7.6 (m, 3H); 8.2 (m, 1H); 10.3 (s, 1H); 12.8 (br. s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Cl)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(Cl)cc1Cl

Procedure:
using isopropyl 2,4-dichloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-dichloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz, 7.78 ppm (s, 1H), 7.65 ppm (s, 1H), 5.23 ppm (m, 1H), 3.42 ppm (s, 3H), 2.96 ppm (m, 2H), 2.82 ppm (m, 2H), 2.17 ppm (m, 2H), 1.35 ppm (d, 6H),
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Oc1ccc(C=c2[nH]c(=O)c(=CCc3ccccc3)[nH]c2=O)nc1)c1ccccc1
Temperature: 150 °C
Yield: 10.3 %

Procedure:
A reaction mixture containing compound B (0.05 g, 0.16 mmole; obtained from Example 14), benzoyl chloride (15 ml, 0.16 mmole) and 50 mL of chloroform was heated to 150° C. for 2 hr. Chloroform was removed in vacuo to produce a residue. The residue was chromatographied using silica gel column with a developing solvent (CH2Cl2) to give 0.007 g (10%) of Compound 15.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][CH2:5][N:6]=1.C(N(CC)CC)C.Cl.[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24])[CH3:17]>ClCCl>[CH3:15][N:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:6]1[CH2:5][CH2:4][N:3]=[C:2]1[CH3:1])=[O:24])[CH3:17]
Reactant: CN(C)CCCCCC(=O)Cl
Reactant: CC1=NCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=NCCN1C(=O)CCCCCN(C)C
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Dichloromethane (400 mL), 2-methyl-2-imidazoline (56.38 g, 0.637 mol), and triethylamine (283.51 g, 2.802 mol) are placed in a 2000 mL three-necked round bottomed flask equipped with a reflux condenser, internal thermometer, mechanical stirrer, addition funnel, and argon inlet. The solution is brought to reflux and 15 min later a solution of 6-(N,N-Dimethylamino)hexanoyl chloride-hydrochloride (150 g, 0.700 mol), prepared as described in example II, dissolved in dichloromethane (300 mL) is added dropwise over 45 min. The mixture is refluxed for an additional 2 h before being cooled to room temperature. The salts are filtered and washed with methylene chloride. The combined flitrates are washed with 5% NaHCO3 solution (3×300 mL) and water (300 mL), After drying over MgSO4 and filtration, the organic layer is concentrated first by rotary evaporation at 50° C. and then by Kugelrohr distillation at 60°-70° C. (0.2 mm Hg) to give 95.20 g (66%) of an oil which solidifies on standing.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9][CH:8]2[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9][CH:8]2[CH2:24][C:25]([OH:27])=[O:26])=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of ethyl [1-(4-fluorobenzyl)-4-(benzyloxycarbonyl)-6-oxo-piperazin-2-yl]acetate (0.5 g, 1.2 mmol) in tetrahydrofuran (2.3 mL) was added 1N sodium hydroxide (2.3 mL, 2.3 mmol). After 2 h, 1N hydrochloric acid (3 mL) was added. The reaction mixture was partitioned between dichloromethane and brine. The organic phase was dried over sodium sulfate, filtered and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 7H), 7.01 (t, J=8.6 Hz, 2H), 5.12-5.20 (m, 3H), 4.45-4.53 (m, 1H), 4.22-4.32 (m, 1H), 3.97 (d, J=15.0 Hz, 2H), 3.78-3.83 (m, 1H), 3.04-3.18 (m, 1H), 2.52-2.67 (m, 2H). ES MS (M+1)=401.2.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15](Cl)=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:24]=1[NH2:25].CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:23]=3[F:22])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)cc(Cl)c2c(=O)n(Cc3ccccc3)cnc21
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1c(=O)cc(Nc2ccc([N+](=O)[O-])cc2F)c2c(=O)n(Cc3ccccc3)cnc21
Yield: 68.6 %

Procedure:
3-Benzyl-5-chloro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (950 mg, 3.15 mmol, 1 eq), 2-fluoro-4-nitroaniline (540 mg, 3.46 mmol, 1.1 eq), tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.06 mmol, 0.02 eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36 mg, 0.06 mmol, 0.02 eq) and sodium tert-butoxide (453 mg, 4.7 mmol, 1.5 eq) were mixed in degassed anhydrous dioxane (7 mL) and subjected to microwave irradiation at 100° C. for 30 minutes. Upon cooling a precipitate formed which was filtered and washed with cold dioxane (3 mL) to give 910 mg of the title compound (69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.55 (s, 3 H) 5.23 (s, 2 H) 6.14 (s, 1 H) 7.29-7.41 (m, 5 H) 7.81-7.94 (m, 1 H) 8.14 (d, J=10.86 Hz, 1 H) 8.25 (d, J=11.12 Hz, 1 H) 8.96 (s, 1 H) 11.23 (s, 1 H) [M+H] calc'd for C21H16FN5O4, 422; found, 422.
Reaction SMILES: [CH2:1]([N:8]([CH2:11][C@@H:12]1[O:17][C:16]2[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH2:13]1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:28][S:29]C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]([CH2:11][C@@H:12]1[O:17][C:16]2[C:18]([F:22])=[C:19]([S:29][CH3:28])[CH:20]=[CH:21][C:15]=2[O:14][CH2:13]1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC
Reactant: CCN(Cc1ccccc1)C[C@H]1COc2cccc(F)c2O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1)C[C@H]1COc2ccc(SC)c(F)c2O1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
A mixture of N-benzyl-N-{[(2S)-8-fluoro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}ethanamine (2.2 g, 7.3 mmol) and 2,2-tetramethylpiperidine (2.5 ml, 14.6 mmol) was added dropwise to n-BuLi (10 ml, 25 mmol) in THF (dry, 10 ml) under N2 at −75° C., followed by the addition of dimethylsulfide (1.32 ml, 14.6 mmol) in THF (dry, 10 ml). The mixture was stirred for 30 min at −75° C., and was then warmed to room temperature. NH4Cl (sat.) was added and the solution was extracted with EtOAc. The combined organic phases were washed with Na2SO3 (15%), brine, dried (Na2SO4) and evaporated to dryness. Flash column chromatography (isooctane/EtOAc) yielded the title compound (1.3 g). MS m/z (rel. intensity, 70 eV) 347 (2), 149 (12), 148 (100), 92 (7), 91 (92).
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][CH:21]([CH3:31])[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[CH3:20][CH:21]([CH3:31])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][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:29][CH:30]=1
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(C)Cc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(2-methylpropyl)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-[[4-(2-methylpropyl)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[N+:5]([O-])[CH:6]=[CH:7][CH:8]=1.C(Cl)(Cl)Cl.P(Cl)(Cl)Cl.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cccnc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, a magnetically stirred solution of 25.8 g (0.185 mole) of 3-methoxy-2-methylpyridine 1-oxide and 200 ml of chloroform cooled to 0° C. was treated dropwise a solution of 75.6 g (0.556 mole) of phosphorus trichloride and 50 ml of chloroform. The temperature was maintained at <10° C. during the addition. The solution was stirred for 20 minutes after the addition was complete, was allowed to warm to room temperature, and was then heated under reflux for an hour. When again at room temperature, the solution was poured into a mixture of ice and water, and the mixture was then adjusted to pH 13 by the addition of 5N sodium hydroxide and solid sodium hydroxide while keeping the mixture cold. The organic phase was separated and the aqueous phase was extracted three times with 50 ml portions of chloroform. The combined organic phase and extracts were dried over anhydrous sodium suflate, filtered, and evaporated under reduced pressure to give 3-methoxy-2-methylpyridine as an oil: b.p. 46° C. at 1.8 mmHg; yield 21.5 g (94%). Lit. b.p. 84.5°-85.5° C. at 17 mmHg [A. L. Logothetis, J. Org. Chem., 29, 1834-1837 (1969)].