Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[N:11][OH:12].[CH2:13]([C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].Cl[O-].[Na+].O>C1COCC1.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH2:21][C:15]([CH2:13][CH3:14])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:12][N:11]=1
Reactant: C=C(CC)C(=O)OCC
Reactant: ON=Cc1cc2ccccc2s1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CC(c2cc3ccccc3s2)=NO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
Benzothiophen-2-aldehyde oxime derivative (400 mg, 2.26 mmol) prepared according to the same procedure as Preparation 1 was dissolved in THF (25 ml), and the mixture was kept at 0□. Ethyl 2-ethylacrylate (434 mg, 1.5 Eq) and triethylamine (7 drops) were dissolved in THF (5 ml), thus obtained solution was slowly added to the above, and sodium hypochlorite solution (6.0 ml) was further added. The reaction solution was warmed to room temperature and stirred for 4 hours. Water (20 ml) was added, and the mixture was extracted with ethyl acetate (40 ml×2), washed with aqueous sodium chloride solution (20 ml), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (20% ethyl acetate-hexane) to give the title compound (121 mg, Yield 18%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:42]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:43]([C:48](ON1C(=O)CCC1=O)=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C=O)C>[NH:42]([C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[C@H:43]([C:48]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)[C@@H](C)O
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)OC)[C@@H](C)O
Yield: 85.9 %

Procedure:
A solution cooled on an ice bath of 5.14 g of TFA, H-Phe-Thr-Asn-Ser-OMe (8.78 mM) in 100 ml of DMF has 3.17 g of Boc-Ile-OSu (9.66 mM), 1.30 g of HOBt (9.62 mM) and N-ethyl morpholine added thereto until a pH of 7 is obtained. After 20 hours of reaction at ambient temperature, the solution is concentrated under reduced pressure and the residue taken up in ether gives a precipitate which is filtered and dried in vacuo. 5.24 g of product are obtained.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C([O:8][CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])(=O)C.C(=O)(O)[O-].[Na+]>C(OC(=O)C)(=O)C>[CH3:17][C:11]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][OH:8]
Reactant: CC(=O)OCc1c(C)cccc1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Reaction time: 2.5 h

Procedure:
Fuming nitric acid (0.52 ml) was added dropwise to a solution of 2,6-dimethylbenzyl acetate (1.78 g) in acetic anhydride (8.9 ml) at 0° C. and then stirred for 2.5 hours. After being stirred for an additional 30 minutes at room temperature, the mixture was poured onto crushed ice, neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with water and evaporated in vacuo. To the residue were added methanol (24 ml) and 1N sodium hydroxide solution (12 ml) and the mixture was stirred at room temperature for 1 hour and evaporated in vacuo. The residue was washed with water, air-dried, and recrystallized from a mixture of benzene and n-hexane to give 2,6-dimethyl-3-nitrobenzyl alcohol (1.26 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[S:11][C:10]2=[N:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][N:9]2[N:8]=1.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[CH3:6][C:7]1[S:11][C:10]2=[N:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:14]([CH:25]=[O:26])[N:9]2[N:8]=1
Reactant: Cc1nn2cc(-c3ccccc3)nc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
60 ml of phosphorus oxychloride were added dropwise to 180 ml of dimethylformamide, whilst cooling. A further 400 ml of dimethylformamide, and 130 g (0.6 mole) of 2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole were then added and the mixture was warmed to 100° C. for 2 hours. It was poured onto 3 kg of ice, 410 g of 40% strength sodium hydroxide solution were added and the mixture was heated rapidly to 90° C. After 5 minutes, it was cooled and the product was filtered off. Yield: 132 g (90% of theory) of melting point 152° to 153° C.
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:31][CH2:30]1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Reactant: FC1(F)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](OC(=O)C(c1ccccc1)N1CCC(F)(F)CC1)c1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
To a solution of the product from Example 138A (1.00 g, 3.13 mmol) in tetrahydrofuran (20 mL) at room temperature was added triethylamine (1.75 mL, 12.5 mmol) and tetrabutylammonium iodide (0.46 g, 1.25 mmol). The mixture was stirred for 5 minutes and then 4,4-difluoropiperidine hydrochloride (0.74 g, 4.70 mmol) was added as the free base in THF. The mixture was stirred for 1 hour at room temperature and then heated to 55° C. overnight. The cooled mixture was washed with brine, concentrated, then purified by column chromatography (EtOAc-hexane) to provide the title compound (1.04 g, 92% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([S:24]([C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[CH3:16])(=[O:26])=[O:25])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (240 mg, 1.1 mmol), 2,4-dimethyl-benzenesulfonyl chloride (278 mg, 1.4 mmol) and di-isopropylethylamine (0.4 mL, 2.3 mmol) were dissolved into DCM (5.0 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (25 mL) and washed with 1N NaOH (10 mL) and water (2×20 mL). The organic layers were combined, dried, filtered and concentrated to yield the title compound (300 mg, 97%).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.N1CCCCC1.[C:14]1([C:20]2[CH:21]=[C:22]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[CH:34]=[C:33](C=O)[CH:32]=[CH:31]4)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[S:40]=[C:41]1[NH:45][C:44](=[O:46])[CH2:43][S:42]1>C(O)(=O)C>[C:14]1([C:20]2[CH:21]=[C:22]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[CH:34]=[C:33]([N:45]3[C:44](=[O:46])[C:43](=[CH2:1])[S:42][C:41]3=[S:40])[CH:32]=[CH:31]4)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1ccccc1
Reactant: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1-c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: C=C1SC(=S)N(c2ccc3cc(-c4ccc(OC)c(-c5ccccc5)c4)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of toluene (2.5 mL), piperidine (0.003 mL), acetic acid (0.004 mL), 6-(3-phenyl-4-methoxyphenyl)-2-naphthaldehyde (0.124 g, 0.37 mmol) and 2-thioxo-4-thiazolidinone (0.049 mg, 0.37 mmol) was heated at reflux for 20.5 hours under an argon atmosphere. The resulting suspension was filtered and the solid was stirred at room temperature in EtOH. After 2 hours, the solid was filtered and dried under high vacuum to afford 0.117 g (70%) of 6-(3-phenyl-4-methoxyphenyl)-naphthalen-2-yl-methylene-2-thioxo4-thiazolidinone, mp 266–269° C. 1H NMR (300 MHz, DMSO-d6): δ 3.82 (s, 3H), 7.25 (d, J=8.4 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.43 (t, J=7.4 Hz, 2H), 7.57 (d, J=7.2 Hz, 2H), 7.67 (d, J=8.7 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.77 (s, 1H), 7.84 (dd, J1=6.0 Hz, J2=2.4 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 8.10 (t, J=9.0 Hz, 2H), 8.19 (s, 1H), 8.30 (s, 1H), 13.96 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[CH:12](OC)(OC)[O:13]C.Cl.O1CCOC[CH2:21]1.CCN(C(C)C)C(C)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:13][CH3:12])([O:11][CH3:21])[CH3:10]
Reactant: C1COCCO1
Reactant: CC(=O)Cc1ccccc1Br
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(Cc1ccccc1Br)OC

Procedure:
2-Bromophenylacetone (4.45000 g, 21 mmol) was dissolved in 10 mL MeOH and trimethyl orthoformate (11 mL, 104 mmol) and hydrogen chloride, 4.0M solution in 1,4-dioxane (5.2 mL, 21 mmol) were added. The mixture was stirred for 1 h and neutralized carefully with DIEA (pH 7). The mixture was evaporated and filtered through a plug of silica providing 1-bromo-2-(2,2-dimethoxypropyl)benzene as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[N:4][N:5]([CH3:7])[CH:6]=1.[CH3:15][NH:16][CH3:17].[O:18]1[CH2:22]CCC1>>[Br:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:22](=[O:18])[N:16]([CH3:17])[CH3:15])=[CH:10][CH:9]=2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: C1CCOC1
Reactant: CNC
Reactant: Cn1cc(Br)c(-c2ccc(N)cc2)n1
Product: CN(C)C(=O)Nc1ccc(-c2nn(C)cc2Br)cc1

Procedure:
Following the procedure described for Example 5a using [4-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]amine and 2M dimethylamine in tetrahydrofuran provided the title compound. ESMS [M+H]+: 323.2
Reaction SMILES: [C:1]1(=O)[N:5]([CH2:6][C:7]2[N:11]([C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=3C(C3C=CC=CC=3)=O)[C:10]([CH2:26][N:27]3C(=O)C4=CC=CC=C4C3=O)=[N:9][N:8]=2)C(=O)[C:3]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:2]12.O.NN>C(O)C>[NH2:27][CH2:26][C:10]1[N:11]2[C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=3[C:1]([C:2]3[CH:3]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[N:5][CH2:6][C:7]2=[N:8][N:9]=1
Reactant: O=C(c1ccccc1)c1ccccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccccc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 22, 2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 1-(aminomethyl)6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12].[Li+].[OH-].CCOC(C)=O>CO.C1COCC1>[C:17]1(/[CH:16]=[CH:15]/[CH2:14][O:13][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:23])=[O:2])=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1NC(=O)OC/C=C/c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1ccccc1C(=O)O)OC/C=C/c1ccccc1
Reaction time: 0.67 h

Procedure:
Compound 72 (7.989 g, 26 mmol) was dissolved in aqueous methanol (3:1, 1200 mL) with THF (2-3 drops) to aid solubility. A solution of LiOH (3.12 g, 130 mmol) was added as a solid to the stirring reaction mixture at 0° C. and stirred for 40 minutes. The reaction was allowed to return to room temperature and stirred for 16 hours, at which time TLC (70% Pet ether:EtOAc) revealed complete reaction. Excess methanol and THF were evaporated in vacuo and the remaining solution acidified to pH 2 with conc. HCl, to furnish a colourless precipitate (73), which was collected by filtration and dried (92%). 1H NMR (250 MHz, CDCl3) δ 10.85 (s, 1H, acid OH), 10.80 (s, 1H, carbamate NH), 8.34-8.32 (d, 1H, aromatic H), 8.00 (dd, 1H, J=1.5, 7.9 Hz, aromatic H), 7.70-7.55 (m, 1H, aromatic H), 7.53-7.10 (m, 5H, aromatic coc), 6.75 (d, 1H, J=16 Hz, 3′-H), 6.46 (dt, 1H, J=6.2, 16 Hz, 2′-H), 4.82 (d, 2H, J=6.3 Hz, 1′-H); 13C NMR (62.9 MHz, CDCl3) δ 170.6 (ester carbonyl), 153.2 (CO carbamate), 142.0 (aromatic quat), 137.1 (aromatic quat), 135.1 (methine), 134.5 (alkenic methine), 132.5 (methine), 131.0 (methine), 127.7 (methine), 125.0 (alkenic methine), 122.6 (methine), 119.0 (methine), 116.5 (aromatic quat), 66.5 (methylene Coc). MS m/z 297 (M+. +1), 265, 252, 236, 224, 205, 189, 176, 149, 138, 117.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:20]([O-])=O)[C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([NH2:20])[C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(N2CCCCC2)c(N)c1

Procedure:
15.45 G. of methyl 3,5-dinitro-4-piperidinobenzoate [Rec. trav. chim. 73, 68 (1954)] dissolved in 200 ml. of methanol were hydrogenated under normal pressure and at room temperature in the presence of 1 g. of palladium/carbon (5%). After uptake of the theoretical amount of hydrogen, the solution was filtered off from the catalyst and evaporated. By recrystallization of the residue from ethyl acetate/petroleum ether, there was obtained methyl 3,5-diamino-4-piperidinobenzoate having a melting point of 133°-134° C.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].B.C1COCC1.C1C2C(=CC=CC=2)C=CC=1CN1CCC[C@H]1CO>C1COCC1.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#CC(=O)CC(=O)CC(=O)OCC
Agent: B
Agent: OC[C@@H]1CCCN1Cc1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CO
Product: C#CC(O)CC(O)CC(=O)OCC
Reaction time: 20 h

Procedure:
50 mg (0.27 mmol) of ethyl 3,5-dioxo-6-heptynoate was dissolved in 5 ml of THF and 52 ml of methanol. Then, with or without addition of aluminum tri-i-propoxide as a metal reagent, a reaction was conducted at 20° C. for 20 hours using 5.4 ml of a 1.0M BH3.THF solution and 6.2 mg (0.027 mmol) of the (S)-N-(β-naphthyl)methyl-2-pyrrolidine methanol (compound (S)-II-1) obtained in Example 1, to obtain ethyl 3,5-dihydroxy-6-heptynoate (VI-2) as oily desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:22]4[N:27]=[C:26]([C:28]5[CH:33]=[CH:32][N:31]=[C:30]([N:34]6[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]6)[CH:29]=5)[CH:25]=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[N:18]=2)[CH:5]=[CH:6][CH:7]=1.C([N:43]([CH2:46][CH3:47])CC)C.[CH3:48]S(Cl)(=O)=O>C(Cl)Cl>[CH:46]1([NH:43][CH:37]2[CH2:38][CH2:39][N:34]([C:30]3[CH:29]=[C:28]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([C:19]5[N:17]6[N:18]=[C:13]([N:9]7[CH2:10][CH2:11][CH2:12][CH:8]7[C:4]7[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=7)[CH:14]=[CH:15][C:16]6=[N:21][CH:20]=5)[N:27]=4)[CH:33]=[CH:32][N:31]=3)[CH2:35][CH2:36]2)[CH2:47][CH2:48]1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN(c2cc(-c3cccc(-c4cnc5ccc(N6CCCC6c6cccc(F)c6)nn45)n3)ccn2)CC1
Solvent: ClCCl
Product: Fc1cccc(C2CCCN2c2ccc3ncc(-c4cccc(-c5ccnc(N6CCC(NC7CC7)CC6)c5)n4)n3n2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(N-cyclopropyl-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-amine) was prepared in the following manner. To a 20 mL reaction flask was added 1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-ol (30 mg, 0.056 mmol) and 0.8 mL of methylene chloride. This solution was charged with triethylamine (0.10 mL, 0.69 mmol) and dropwise addition of methane sulfonyl chloride (MsCl, approx. 20 mg, 0.18 mmol). The resulting solution was stirred for 2 hours, followed by quenching with water, ethyl acetate extraction (3×30 mL), and the organic extracts were transferred to a 10 mL volume resealable vessel. The residue in the vessel was charged with 2 mL cyclopropylamine (excess, co-solvent) and 0.5 mL of THF. The vessel was sealed and heated for 6 hours at 90° C. Upon cooling, the contents of the vessel were concentrated to a volume of 1 mL and directly subjected to reverse phase separation (gradient, C-18 support, 10 to 70%, acetonitrile:water) to give (N-cyclopropyl-1-(6-(6-(2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,4′-bipyridin-2′-yl)piperidin-4-amine). 1H NMR (400 MHz, D3 acetonitrile) δ ppm 8.71 (br s, 1H), 8.41 (s, 1H) 8.26 (d, J=7.2 Hz, 1H), 7.99 (app d, J=6.7 Hz, 2H), 7.85 (d, J=6.2 Hz, 1H), 7.73 (br s, 1H), 7.63 (s, 1H), 7.42 (d, J=6.4 Hz, 1H), 7.39 (app q, J=6.8 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 7.05 (dt, J=8.6, 1.9 Hz, 1H), 6.99-6.82 (m, 1H), 5.27 (d, J=6.4 Hz, 1H), 4.54 (app d, J=10 Hz, 2H), 4.00 (app q, J=3.9 Hz, 1H), 3.69-3.62 (m, 1H), 3.46 (app d, J=5.8 Hz, 1H), 2.98 (app q, J=4.2 Hz, 2H), 2.73 (br s, 2H), 2.47-2.35 (m, 1H), 2.13 (app dd, J=5.6 Hz, 2H), 2.08-2.03 (m, 2H), 1.89-1.86 (m, 1H), 0.82-0.66 (m, 5H). LRMS observed m/z 575.3 major ion (calcd for M+H, 575.3).
Reaction SMILES: O[CH2:2][P:3]([CH2:6]O)[CH2:4]O.C=O.[S:10]([NH2:14])([NH2:13])(=[O:12])=[O:11].[CH2:15]1N2CN3CN(C2)[CH2:17][N:16]1C3>O>[N:13]12[CH2:17][N:16]3[CH2:2][P:3]([CH2:6][N:14]([CH2:15]3)[S:10]1(=[O:12])=[O:11])[CH2:4]2
Reactant: OCP(CO)CO
Reactant: NS(N)(=O)=O
Reactant: C1N2CN3CN1CN(C2)C3
Agent: C=O
Solvent: O
Product: O=S1(=O)N2CN3CN1CP(C3)C2
Yield: 66 %

Procedure:
Tris(hydroxymethyl)phosphine (3.9 g, 80%, 0.025 moles) was dissolved in formalin (20 ml, 40%, 0.267 moles) and water (20 ml). Sulfamide (2.4 g, 0.025 mole) and hexamethylenetetramine (3.5 g, 0.025 mole) were added together and dissolved in the solution at room temperature. The solution heated up slightly and over the next twenty-four hours a precipitate formed. Filtration, dissolution of the solid in 4 successive 30 ml acetone washes and evaporation of the acetone yielded 3.42 g of crude 2-thia-1,3,5-triaza-7-phosphaadamantane 2,2-dioxide (66% yield) [mp 274°-5° (water)].
Reaction SMILES: [CH3:1][N:2]1[C:7](=[N:8][N+:9]([O-:11])=[O:10])[NH:6][CH2:5][O:4][CH2:3]1.[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[S:14][C:15]([CH2:18][N:6]2[CH2:5][O:4][CH2:3][N:2]([CH3:1])[C:7]2=[N:8][N+:9]([O-:11])=[O:10])=[CH:16][N:17]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Yield: 67 %

Procedure:
A mixture of 1.62 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine, 2.44 g of 2-chloro-5-chloromethyl-thiazole, 4.2 g of potassium carbonate and 25 ml of N,N-dimethylformamide is heated for 5 h at 60° and then filtered. The filtrate is evaporated in vacuo on a rotary evaporator, and the residue is purified by chromatography [silica gel; dichloromethane/methanol (95:5)]. This gives the title compound, which melts at 132-134°, in a yield of 67%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[S:8]C#N.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[SH:8]
Reactant: N#CSc1ccc(O)cc1Br
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(S)c(Br)c1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a hot (85° C.) solution of 3-bromo-4-thiocyanato-phenol (315 mg, 1.37 mmol) in absolute ethanol (10 mL) under nitrogen, sodium sulfide nonahydrate (403 mg, 2.05 mmol) was added. The resulting mixture was stirred at 85° C. for 20 min. More sodium sulfide nonahydrate (230 mg) was added and heating was continued for 15 min. The mixture was cooled down, made acidic with 5N acetic acid (10 mL) and extracted with methylene chloride (×1). The organic layer was washed once with water, dried and concentrated in vacuo to give the title compound as a yellow solid (259 mg, 92%) which was quickly submitted to the next reaction without further treatment. EIMS M−1: 203.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[OH:18])=[CH:10][CH:9]=[N:8]1>CCCCCC.C(O)(C)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])=[CH:10][CH:9]=[N:8]1
Reactant: COCCOCn1nccc1[C@H]1CCCC[C@@H]1O
Solvent: CCCCCC
Solvent: CC(C)O
Product: COCCOCn1nccc1[C@@H]1CCCC[C@H]1O

Procedure:
The (1S*,2R*)-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexanol prepared in Example 158a was optically resolved with CHIRALFLASH IC (Daicel Corp.; hexane/isopropanol=1:1) to yield the title compound as a colorless oil.
Reaction SMILES: F[B-](F)(F)F.[F:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:37]([O:44][CH2:45][C:46](=O)[CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>C1COCC1>[Si:37]([O:44][CH2:45][C:46](=[CH:7][F:6])[CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: FC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=CF)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vigorously stirring suspension of fluoromethyl(triphenyl)-phosphonium tetrafluoroborate (18.9 g, 49.4 mmol) in dry THF (190 mL) at −20° C. under N2 was added sodium bis(trimethylsilyl)amide (1.0 M in THF; 49.4 mL, 49.4 mmol) slowly over 10 min. The resulting deep orange solution was left to stir at this temperature for 15 min. A solution of tert-butyl 3-(tert-butyldimethylsilyloxy)-2-oxopropylcarbamate (10.0 g, 33.0 mmol) in THF (10 mL) was then added slowly over 10 min. After complete addition, stirring was continued for a further 1 h during which time the reaction was allowed to warm slowly to room temperature. The reaction was quenched by addition of water (5 mL) and the reaction mixture was concentrated in vacuo. The residue was partitioned between water (100 mL) and diethyl ether (100 mL) and the aqueous layer was extracted with further diethyl ether (2×100 ml). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified over silica gel eluting with n-hexane followed by 6% ethylacetate in n-hexane to give tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-fluoroallylcarbamate as a mixture of E/Z double-bond isomers (E/Z=1:1; 9.9 g; 94%). The isomers were not separated at this stage.