Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[N:17]([C:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[S:4][N:3]=2)[N:16]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(-c2nsc3ccc([N+](=O)[O-])cc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 3-chloro-5-nitrobenzisothiazole (5.3 g, mmol), 3,5-dimethylpyrazole (2.40 g, 25.0 mmol) and pyridine is stirred overnight at reflux, cooled to room temperature and diluted with ethyl acetate. The resultant mixture is filtered and the filtrate is washed with three portions of 10% hydrochloric acid and one portion of water. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound (2.85 g, 43.8%) which is identified by NMR spectral analysis.
Reaction SMILES: S(=O)(=O)(O)O.CO[CH:8](OC)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:10].[OH-].[Na+]>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:15]=[C:14]2[C:13](=[CH:18][CH:17]=1)[CH:12]=[N:11][C:9]([OH:10])=[CH:8]2
Reactant: COC(OC)C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc2cc(C(F)(F)F)ccc2cn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Sulfuric acid (18 M; 2.25 mL, 40.5 mmol) was added to 2,2-dimethoxy-N-(4-trifluoromethylbenzyl)-acetamide (828 mg, 2.96 mmol) at rt. The combined solution was stirred at 50° C. overnight. The mixture was poured into ice, basified with NaOH (10 N) until pH>12, and extracted with EtOAc (3×50 ml). The extracts were washed with water (20 ml), dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with 50% EtOAc/hexane (10 ml) to yield a yellow solid that was then purified by Gilson HPLC to give the title compound as yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.18 (s, 1H), 7.45-7.51 (m, 1H), 7.96-8.02 (m, 2H), 8.89 (brs, 1H). MS(ES+): m/z=214.32 (100) [MH+]. HPLC: tR=2.64 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1.Cl[CH2:27][C:28]1[CH:47]=[CH:46][C:31]([O:32][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:37][C:38]=2[CH3:39])=[C:30]([O:48][CH3:49])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:49][O:48][C:30]1[CH:29]=[C:28]([CH:47]=[CH:46][C:31]=1[O:32][CH2:33][C:34]1[N:35]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][C:38]=1[CH3:39])[CH2:27][O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (3.06 g), potassium carbonate (2.50 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.43 g, yield: 95%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from acetone-hexane. Melting point: 127–128° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH2:47])[O:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:40][CH:39]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:47][C:45]1[O:46][C:42]2[C:41]([CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:40][CH:39]=[C:38]([O:37][CH3:36])[C:43]=2[N:44]=1)=[O:8]
Reactant: O=C(O)c1ccnc(CCl)c1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12

Procedure:
From 2-chloromethyl-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 404 (M{37Cl}+H+, 30), 402 (M{35Cl}+H+, 100).
Reaction SMILES: [OH-].[Na+].Br[C:4]([CH3:10])([CH3:9])[C:5]([NH:7][CH3:8])=[O:6].FC(F)(F)C(O)=O.[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[N:28]([CH2:29][CH2:30][O:31][C:32]4[CH:39]=[C:38]([CH:40]5[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]5)[CH:37]=[CH:36][C:33]=43)[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH:18]([N:21]1[C:25]([C:26]2[N:35]=[C:34]3[C:33]4[CH:36]=[CH:37][C:38]([CH:40]5[CH2:45][CH2:44][N:43]([C:4]([CH3:10])([CH3:9])[C:5]([NH:7][CH3:8])=[O:6])[CH2:42][CH2:41]5)=[CH:39][C:32]=4[O:31][CH2:30][CH2:29][N:28]3[CH:27]=2)=[N:24][CH:23]=[N:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CNC(=O)C(C)(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(C)(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
A biphasic mixture of 50% aqueous sodium hydroxide (2 mL) and DCM (2.5 mL) was treated with 2-bromo-2,N-dimethyl-propionamide (121 mg, 0.67 mmol), tetrabutylammonium bromide (118 mg, 0.37 mmol) and a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (300 mg, 0.61 mmol) in DCM (1 mL). The resultant mixture was stirred at RT for 3 h before the addition of further tetrabutylammonium bromide (118 mg, 0.37 mmol) and stirring at RT for 18 h. The reaction mixture was diluted with DCM and washed with water. The combined aqueous extracts were washed with DCM and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) followed by trituration in diethyl ether to give 248 as a cream solid (120 mg, 41%). 1H NMR δ (ppm) (DMSO-d6): 8.27 (1H, d, J=8.26 Hz), 7.86 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.64 (1H, m), 7.02 (1H, dd, J=8.34, 1.75 Hz), 6.91 (1H, d, J=1.70 Hz), 5.88-5.78 (1H, m), 4.48-4.42 (4H, m), 2.74 (2H, d, J=10.86 Hz), 2.59 (3H, d, J=4.75 Hz), 2.17-2.08 (2H, m), 1.75-1.69 (4H, m), 1.43 (6H, d, J=6.60 Hz), 1.05 (6H, s). 1 Proton obscured by solvent peak. LCMS: RT=2.78 min, M+H+=478
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][OH:30])[OH:19])[CH3:9].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>ClCCl>[O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][O:30][S:39]([CH3:38])(=[O:41])=[O:40])[OH:19])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC1C(O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC1C(O)CCC(O)(CSCc2ccccc2COS(C)(=O)=O)C1C1(C)OC1CC=C(C)C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
In dichloromethane (0.5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (100 mg) and triethylamine (64 μl). To the solution was added dropwise, under ice-cooling, methanesulfonylchloride (20 μl ). The mixture was stirred for 15 minutes, to which was added water to suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane=2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (98 mg: yield 83%) as a colorless oily product.
Reaction SMILES: FC(F)(F)C1C=C(C2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)C=CC=1.FC(F)(F)CC1C=CC=CC=1N1CCN(C2N=CC(N)=CC=2)CC1.ClC1C=CC([N+]([O-])=O)=CN=1.[F:58][C:59]([F:73])([F:72])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[N:66]1CCNCC1>>[F:58][C:59]([F:72])([F:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[N:66]1[CH2:10][CH2:11][N:12]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: FC(F)(F)c1ccccc1N1CCNCC1
Reactant: Nc1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1
Agent: Nc1ccc(N2CCN(c3ccccc3CC(F)(F)F)CC2)nc1
Agent: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCN(c3ccccc3C(F)(F)F)CC2)nc1

Procedure:
With a method similar to that used for the preparation of 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine above, 6-[4-(2-trifluoroethyl-phenyl)-piperazin-1-yl]-pyridin-3-ylamine was prepared from 2-chloro-5-nitropyridine and 1-(2-trifluoromethyl-phenyl)-piperazine followed by hydrogenation. LCMS calcd for C16H17F3N4 (m/e) 322, obsd 323 (M+H).
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4[C:22](=NC=CC=4)[O:21][C:20]4C=CC=C(O)[C:19]=4C3)CC2)=CC=1.[Cl:34][C:35]1[CH:36]=[C:37]2[C:65](=[CH:66][CH:67]=1)[C:40]1([CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH:48]=[C:49]3[C:59]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[O:53][C:52]4[CH:60]=[CH:61][CH:62]=[C:63]([OH:64])[C:51]=4[CH2:50]3)[CH2:42][CH2:41]1)[O:39][CH2:38]2>>[Cl:34][C:35]1[CH:36]=[C:37]2[C:65](=[CH:66][CH:67]=1)[C:40]1([CH2:41][CH2:42][N:43]([CH2:46][CH2:47][CH:48]=[C:49]3[C:59]4[C:54](=[N:55][CH:56]=[CH:57][CH:58]=4)[O:53][C:52]4[CH:60]=[CH:61][CH:62]=[C:63]([O:64][CH2:19][CH2:20][O:21][CH3:22])[C:51]=4[CH2:50]3)[CH2:44][CH2:45]1)[O:39][CH2:38]2
Reactant: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: Oc1cccc2c1CC(=CCCN1CCC3(CC1)OCc1cc(Cl)ccc13)c1cccnc1O2
Product: COCCOc1cccc2c1CC(=CCCN1CCC3(CC1)OCc1cc(Cl)ccc13)c1cccnc1O2

Procedure:
The titled compound was prepared by following the procedure of example 175, but replacing the product of example 44 with the product of example 196.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][N:3]=1.[F:45][C:46]1[CH:47]=[C:48]([NH2:54])[CH:49]=[N:50][C:51]=1[O:52][CH3:53].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:45][C:46]1[CH:47]=[C:48]([NH:54][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=3)=[CH:4][N:3]=2)[CH:49]=[N:50][C:51]=1[O:52][CH3:53]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.58 h
Yield: 53.3 %

Procedure:
4-(2-Fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (602.4 mg, 0.9816 mmol) and 5-fluoro-6-methoxypyridin-3-amine (159.0 mg, 1.119 mmol) were dissolved in THF (10 mL) and the reaction flask was cooled in an ice water bath. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 3.0 mL, 3.0 mmol) was added via syringe, and the reaction was stirred under nitrogen for 35 min. Then, the reaction was diluted with water (20 mL) and then extracted with DCM. Brine was added to the biphasic mixture and extraction with DCM was continued. Water and MeOH were also added to the aqueous phase to help break up emulsions. The organic extracts (about 350 mL total) were combined and washed with brine (50 mL). The brine layer was extracted with DCM, and all of the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; 100:1 DCM/MeOH) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (384.7 mg). 1H NMR (CDCl3, 400 MHz) δ 11.82 (br s, 1H), 8.63 (d, J=1.96 Hz, 1H), 8.17 (d, J=2.15 Hz, 1H), 8.00 (d, J=12.32 Hz, 1H), 7.95 (d, J=2.15 Hz, 1H), 7.82 (d, J=8.02 Hz, 2H), 7.37 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.41 Hz, 2H), 7.15 (d, J=8.41 Hz, 2H), 6.90-6.81 (m, 4H), 4.86 (s, 2H), 4.77 (s, 2H), 4.01 (s, 5H), 3.82 (s, 3H), 3.80 (s, 3H), 2.96 (s, 3H), 2.58 (s, 3H). m/z (ESI, pos. ion) 736 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 95 %

Procedure:
A stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3.07 g, 15 mmol), tert-butyl piperazine-1-carboxylate (3.35 g, 18.00 mmol) and DIPEA (3.85 mL, 22.50 mmol) in DMF (25 mL) was heated at 100° C. for 1 hour. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was triturated with ether and the solid was collected by filtration, washed with ether and dried under vacuum to afford tert-butyl 4-[3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (5.05 g, 95%) as a white crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1.[OH-].[Na+].Cl>CO.O1CCOCC1.O>[C:20]1([CH2:19][O:18][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=2)[C:3]([OH:26])=[O:2])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 96.2 %

Procedure:
A solution of 41.4 g (0.12 mol) of 3,5-bis(phenylmethoxy)benzoic acid methyl ester and 59 ml (0.36 mol) of 6N NaOH in 700 ml of methanol and 350ml of dioxane was stirred at reflux for 17 hours. The solvents were removedat reduced pressure and the residue was dissolved in water and acidified topH 3 with 6N HCl. The resultant solid was filtered and recrystallized from methylene chloride-methanol to give 38.6 g (97% yield, mp 211°-213°) of 3,5-bis(phenylmethoxy)benzoic acid.
Reaction SMILES: [CH2:1]([N:4]([CH3:26])[C:5](=[O:25])[C:6]1[C:18]([I:19])=[C:17]([N:20]=[C:21]=[O:22])[C:16]([I:23])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:24])[CH:2]=[CH2:3].[CH2:27]([OH:31])[CH2:28][CH2:29][OH:30]>ClCCl>[CH2:13]([N:11]([CH3:12])[C:9]([C:8]1[C:16]([I:23])=[C:17]([NH:20][C:21]([O:30][CH2:29][CH2:28][CH2:27][O:31][C:21](=[O:22])[NH:20][C:17]2[C:16]([I:23])=[C:8]([C:9](=[O:10])[N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[C:7]([I:24])=[C:6]([C:5](=[O:25])[N:4]([CH2:1][CH:2]=[CH2:3])[CH3:26])[C:18]=2[I:19])=[O:22])[C:18]([I:19])=[C:6]([C:5](=[O:25])[N:4]([CH2:1][CH:2]=[CH2:3])[CH3:26])[C:7]=1[I:24])=[O:10])[CH:14]=[CH2:15]
Reactant: OCCCO
Reactant: C=CCN(C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)CC=C)c1I
Solvent: ClCCl
Product: C=CCN(C)C(=O)c1c(I)c(NC(=O)OCCCOC(=O)Nc2c(I)c(C(=O)N(C)CC=C)c(I)c(C(=O)N(C)CC=C)c2I)c(I)c(C(=O)N(C)CC=C)c1I
Reaction time: 18 h

Procedure:
To a solution of N,N′-Diallyl-2,4,6-triiodo-5-isocyanato-N,N′-dimethyl-isophthalamide in dichloromethane was added 1,3-propane diol (0.5 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give) [3,5-Bis-(allyl-methyl-carbamoyl)-2,4,6-triiodo-phenyl]-carbamic acid 3-[3,5-bis-(allyl-methyl-carbamoyl)-2,4,6-triiodo-phenyl]carbamoyloxy-propyl ester. A cis-dihydroxylation using OsO4 and NMMO was performed and the crude mixture was purified by preparative HPLC to give {3,5-Bis-[bis-(2,3-dihydroxy-propyl)-carbamoyl]-2,4,6-triiodo-phenyl}-carbamic acid 3-{3,5-Bis-[bis-(2,3-dihydroxy-propyl)-carbamoyl]-2,4,6-triiodo-phenylcarbamoyloxy}propyl ester as a white powder after freeze drying.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[N:29]=[C:30]([CH3:40])[S:31][C:32]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])=[O:27])[CH2:20]2.Cl[C:42]1[N:47]=[C:46]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:45]=[CH:44][N:43]=1>>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]1[S:31][C:30]([CH3:40])=[N:29][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:42]2[N:47]=[C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:45]=[CH:44][N:43]=2)[CH2:20]1)=[O:27]
Reactant: Cc1nc(C(=O)N2CC3CNC3C2)c(-c2ccccc2F)s1
Reactant: Clc1nccc(-c2ccccc2)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: Cc1nc(C(=O)N2CC3CN(c4nccc(-c5ccccc5)n4)C3C2)c(-c2ccccc2F)s1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 21 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C26H22FN5OS, 471.56; m/z found, 472.1 [M+H]+.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].BrCCCBr.C(N(CC)CC)C>CN(C=O)C>[C:6]1(=[O:7])[NH:2][C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: BrCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 47.5 °C
Reaction time: 5.5 h

Procedure:
A mixture of N-hydroxyphthalimide (100 mmol) and 1,3-dibromopropane (100 mmol) in dry DMF and triethyl amine (110 mmol) is stirred at 20-75° C. for 1-10 hours. After filtration, the mixture is evaporated to dryness under reduced pressure. The residue is purified by silica gel chromatography to give N-[(3-bromopropyl)oxy)]phthalimide.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:16][CH3:17])=[C:6]([Cl:15])[CH:7]=[C:8]([N+:12]([O-])=O)[C:9]=1[O:10][CH3:11])([O-:3])=[O:2].C1CCCCC=1>[Pd].C(O)C>[NH2:12][C:8]1[C:9]([O:10][CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:16][CH3:17])=[C:6]([Cl:15])[CH:7]=1
Reactant: COc1c(Cl)cc([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1c(N)cc(Cl)c(OC)c1[N+](=O)[O-]

Procedure:
The mixture consisting of 0.2 mole (52.5 g) of 3,5-dinitro-2,4-dimethoxychlorobenzene, 15.9 g of palladium on charcoal (10%) in 260 ml of absolute ethanol containing 110 ml of cyclohexene was heated to reflux for 1 hour. The catalyst was removed by filtration. After evaporation to dryness under vacuum, an oil was obtained which crystallized after an addition of iced water. After thorough draining and drying, the product obtained was recrystallized from a benzene and cyclohexane mixture. It melted at 68° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[N:7][C:6]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:5]=2[CH:4]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[OH:35]>O.CN(C)C=O>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[O:35][CH2:2][C:3]1[N:8]=[N:7][C:6]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[O:12][C:5]=2[CH:4]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: BrCc1cc2c(nn1)Oc1ccccc1O2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)Oc1cc(COc3ccc4ccccc4c3)nnc1O2
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To 3-(bromomethyl)[1,4]benzodioxino[2,3-c]pyridazine (500 mg) were added dimethylformamide (10 ml), potassium iodide (30 mg), potassium carbonate (750 mg) and 2-naphthylalcohol (290 mg), and the mixture was stirred at room temperature for 24 hr. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was washed with diethyl ether and the resulting solid was filtered and dried under reduced pressure to give 3-[(2-naphthyloxy)methyl][1,4]benzodioxino[2,3-c]pyridazine (400 mg).
Reaction SMILES: O.C(OCC)(=O)C.[Br:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]3[CH:29]=[CH:30][N:31]=[C:19]23)=[C:11]([F:32])[CH:10]=1>[Fe].C(O)(=O)C>[NH2:15][C:14]1[C:9]([Br:8])=[CH:10][C:11]([F:32])=[C:12]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]3[CH:29]=[CH:30][N:31]=[C:19]23)[CH:13]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc([N+](=O)[O-])c(Br)cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Br

Procedure:
To a mixed solution of water (100 ml), ethyl acetate (50 ml) and acetic acid (50 ml) was added 8-(4-bromo-2-fluoro-5-nitrophenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (12.5 g) synthesized in Example 16 and iron powder (8.0 g) and heated to reflux for 3 hours. The reaction solution was filtered through Celite and then the Celite was washed with heated ethyl acetate. The combined filtrate and washing was washed with water, saturated sodium hydrogencarbonate and water in this order, and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure after removing a portion adjacent to the original point of the short column of alumina. The thus obtained solid was recrystallized from isopropyl alcohol/isopropyl ether=1/9 to give the compound of interest (9.3 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1.S(Cl)([Cl:13])(=O)=O>ClCCl>[Cl:13][CH2:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Cl:9])=[CH:5][N:4]=1
Reactant: CSc1ncc(Cl)cn1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: ClCSc1ncc(Cl)cn1
Yield: 82 %

Procedure:
2-Methylthio-5-chloropyrimidine (75 mmol) and sulfuryl chloride (104 mmol) were heated together in refluxing dichloromethane (100 ml) for 3 h. Evaporation of the mixture left a solid which was recrystallized from ethanol; yield 82%, m.p. 78° C. 1H NMR (CDCl3): 5.20 (SCH2), 8.54 (H-4, H-6).