Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([OH:35])=O)[CH2:32][CH2:31]1)=[O:29].[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[O:35])[CH2:31][CH2:32]1)=[O:29]
Reactant: CN1CCC(N)CC1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
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: CCN(CC)CC
Product: CN1CCC(NC(=O)C2(C(=O)Nc3ccc(Oc4ccnc(NC(=O)N(C)C5CCN(C)CC5)c4)cc3F)CC2)CC1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added 4-amino-1-methylpiperidine (18.8 mg), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 8 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (20.0 mg, 42%).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.CI.O>C1COCC1>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH2:16][CH3:2])[CH:8]=1
Reactant: [Li]CCCC
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Yield: 67 %

Procedure:
To a yellow solution of 2,2,6,6-TMPH (8.30 g, 58.88 mmol) in THF (9 mL) was added n-BuLi (25 mL) slowly at −78° C. under protection of nitrogen. Thereto, the mixture was warmed up to room temperature, stirred at this temperature for an hour, and then cooled to −78° C. again. A solution of 4-bromo-2-methylbenzoic acid (6.0 g, 28.04 mmol) in THF (60 mL) was added slowly, kept stirring at this temperature for an hour, added MeI (7.96 g, 56.07 mmol) solution (in 35 mL THF), the mixture above was then stirred overnight at room temperature. LCMS showed the reaction was completed. Water was added, the mixture was then washed with ethyl acetate. The aqueous phase was acidified to pH=1, extracted with ethyl acetate twice, and concentrated the organic phase to a residue which was trituated with PE/EA=1/1 to give 4.28 g of the title compound (67%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl>O.CS(C)=O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][N:23]=[C:22]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 140 °C
Yield: 58.7 %

Procedure:
6-Hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 38 ml of DMSO were stirred at room temperature while cesium carbonate (7.5 g, 22.9 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (2.05 g, 9.14 mmol) were added. The mixture was heated at 140° C. for 3 hours. The mixture was cooled to room temperature and diluted with 40 mL of H2O. The mixture was neutralized with 2 N HCl to 6.5. The deposited solids were collected by vacuum filtration, washed with H2O, dried under vacuum and recrystallized from methanol to give the title compound (1.68 g, 59% yield) as a brown solid. LC-MS (m/z) 377 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[O:11].[CH2:19]=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>C(O)(=O)C.O>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:10]([C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:19][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[CH2:17][CH2:16]1
Reactant: C=O
Reactant: C1CCNC1
Reactant: CN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(C(=O)c2[nH]c3ccccc3c2CN2CCCC2)CC1

Procedure:
(1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 4, 0.231 g) in acetic acid (1.5 mL) at ambient temperature was treated with paraformaldehyde (0.4 g) and pyrrolidine (0.16 mL). The reaction mixture was heated at 60° for 6 h then poured into water and the solution adjusted to basic pH by addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.1 g).
Reaction SMILES: [O:1]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:15][C:12]1[CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH2:14])=[N:10][CH:11]=1
Reactant: Nc1ncccc1Oc1ccccc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Phenoxypyridin-2-amine (20.50 g, 110.1 mmol) was placed in acetic acid (50 mL) and cooled to 0° C. Bromine (d 3.12) (7.049 mL, 137.6 mmol) was slowly added and the reaction mixture was stirred for 1 hour. The reaction mixture was poured onto saturated sodium bisulfite and ice and allowed to sit overnight. Solids were removed by filtration and washed with water to give pure 5-bromo-3-phenoxypyridin-2-amine. The filtrate was then extracted with CH2Cl2 several times, combined, and washed with water. Organic layer was dried, filtered, and concentrated. The residue was purified by silica gel (5-20% EtOAc in hexanes) to give additional 5-bromo-3-phenoxypyridin-2-amine (total yield: 22.69 g, 77.74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:26])[C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CI
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 162.7 %

Procedure:
To a mixture of ethyl 6-chloro-1,2-dihydro-2-oxo-4-phenyl-3-quinolinecarboxylate (2.62 g) and DMF (24 ml) was added portionwise 60% sodium hydride in oil (0.35 g), followed by stirring for 30 minutes at room temperature. The mixture was ice-cooled, to which methyl iodide (0.6 g) was dropwise added under stirring. The mixture was stirred for 3 hours at room temperature, diluted with and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to remove the solvent. The residue was crystallized from isopropyl ether to give crystals of ethyl 6-chloro-1,2-dihydro -1-methyl-2-oxo-4-phenyl-3-quinolinecarboxylate (2.35 g, 92.7%). Recrystallization from ethanol gave colorless needles. mp 124°-125° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15]2[N:19]3[N:20]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:23][C:18]3=[CH:17][N:16]=2)[C@H:3]1[CH3:31].FC1C=CC=C(F)C=1C1C=CC2N(C(NC3C=NC=CC=3N3CCCC(NC(=O)OC(C)(C)C)C3C)=NC=2)N=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15]2[N:19]3[N:20]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:23][C:18]3=[CH:17][N:16]=2)[C@H:3]1[CH3:31]
Reactant: C[C@H]1[C@H](N)CCCN1c1ccncc1Nc1ncc2ccc(-c3ncccc3F)nn12
Agent: CC1C(NC(=O)OC(C)(C)C)CCCN1c1ccncc1Nc1ncc2ccc(-c3c(F)cccc3F)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1[C@@H](N)CCCN1c1ccncc1Nc1ncc2ccc(-c3ncccc3F)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-(4-((trans)-3-amino-2-methyl-1-piperidinyl)-3-pyridinyl)-2-(3-fluoro-2-pyridinyl)imidazo[1,5-b]pyridazin-7-amine (enantiomer 1) (Example 54). tert-Butyl (1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)pyridin-4-yl)-2-methylpiperidin-3-yl)carbamate (first eluting enantiomer) (53 mg, 0.09 mmol) in 2 mL of DCM was treated with 0.5 mL of TFA and stirred at RT for 1 h. Volatiles were removed under reduced pressure. The residue was treated with 10 mL of 1 N NaOH, and the mixture was extracted with 3×15 mL of EtOAc. The combined organic extracts were washed with 2×5 mL of water followed by 2×5 mL of brine, dried over sodium sulfate and concentrated to give the title compound (39 mg, 96% yield) as an orange amorphous solid. MS (ESI, pos. ion) m/z: 436.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.47 (1 H, s), 8.00-8.17 (2 H, m), 7.63 (1 H, tt, J=8.5, 6.5 Hz), 7.39 (1 H, s), 7.30 (2 H, m), 7.16 (1 H, d, J=5.1 Hz), 6.70 (1 H, d, J=9.4 Hz), 3.37 (3 H, br.), 2.78 (2 H, m), 2.56 (1 H, m), 2.36 (1 H, m), 1.76 (1 H, m), 1.59 (2 H, m), 1.23 (1 H, m), 0.84 (3 H, d, J=6.3 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −113.35. The relative stereochemistry was confirmed by 1H-NMR studies.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].BrCC(C1C=CC(C2C=CC(F)=CC=2F)=CC=1)=O.[C-:36]#[N:37].[K+]>>[C:36]([CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=1)=[O:3])#[N:37]
Reactant: [C-]#N
Reactant: CC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=C(CBr)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Product: N#CCC(=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Grignard reagent obtained from 14.2 g. of methyl iodide and 2.4 g. of magnesium in 100 ml. of THF is added dropwise to a solution of 30.4 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-oxopropionic acid ethyl ester, obtained by brominating 4-acetyl-2',4'-difluorobiphenyl to 4-bromoacetyl-2',4'-difluorobiphenyl, reacting this with KCN to give 4-cyanoacetyl-2',4'-difluorobiphenyl, hydrolyzing the latter and esterifying the reaction product, in 200 ml. of THF. When the addition is complete, the mixture is heated and stirred for 2 hours more on a water bath and cooled. The resulting alcoholate is hydrolyzed with ice and saturated NH4Cl solution. The ether phase is dried and evaporated to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester, m.p. 96°-97°.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])[CH3:3].[N-:16]=[N+]=[N-].[Na+].O.C(=O)([O-])[O-].[K+].[K+]>C(O)(C(F)(F)F)=O>[CH3:1][CH:2]([O:4][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:15])[NH:16][C:11]=2[CH:12]=[CH:13][CH:14]=1)[CH3:3]
Reactant: CC(C)Oc1cccc2c1CCCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Oc1cccc2c1CCCC(=O)N2
Yield: 60.9 %

Procedure:
A mixture of 4.39 g of 5-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one and 1.74 g of sodium azide in 70 ml of TFA is refluxed for 2 hours. The reaction medium is poured into 250 ml of water, brought to pH 7 by adding potassium carbonate and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and MeOH (100/0 to 90/10). 2.87 g of 6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are obtained in the form of a beige solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.Cl[P:22]([CH3:24])[CH3:23].Cl[Sn:26]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30]>CCOCC>[CH2:35]([Sn:26]([C:2]1[CH:3]([P:22]([CH3:24])[CH3:23])[C:4]2[C:9]([CH:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])[CH2:36][CH2:37][CH3:38]
Reactant: CP(C)Cl
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)C1=Cc2ccccc2C1P(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
150 ml of ether were placed in a round-bottomed flask containing 5.5 g (0. 047 moles) of indene; the solution was cooled to −20° C. 20.8 ml of a 2.3 molar solution of butyllithium in hexane (0.048 moles) were added over 5 min to form a yellow solution. After removal of the cooling bath, the solution was heated to room temperature and subsequently stirred for 1 h. After cooling of the reaction mixture to −30° C., 4.6 g of chlorodimethylphosphine (0.048 moles) in 30 ml of ether were added over 20 min to form a precipitate. After stirring for 2 hours at −20° C., 20.8 ml of a 2.3 molar solution of butyllithium in hexane (0.048 moles) were added dropwise. When the addition was complete, the cooling bath was removed and the solution was heated slowly to room temperature and stirred for 1.5 h. After cooling of the suspension to 0° C., 15.6 g of chlorotributyltin (0.048 moles) were added dropwise. The suspension formed was heated to room temperature and stirred for 1.5 h. The ether was removed under vacuum, the crude product was dissolved in hexane again, the solution was filtered and the filtrate was concentrated to dryness under vacuum to leave 17.4 g of compound 10 (yield: 78%) in the form of a heavy yellow oil. 1H NMR (400 MHz, CD2Cl2): δ=7.67 (d, J=7.5 Hz, 1H); 7.47 (d, J=7.4 Hz, 1H); 7.18 (m, 2H); 6.83 (m, 1H); 4.28 (s with Sn satellites, 1H); 1.43-0.78 (m, 33H); 3P NMR (161.9 MHz, CD2Cl2): δ=−61.6 ppm.
Reaction SMILES: O.[C:2]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])#[N:3].[H][H]>[Ir].CO>[C:7]1([C@@H:5]([OH:6])[CH2:4][C:2]#[N:3])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: [H][H]
Agent: [Ir]
Solvent: CO
Solvent: O
Product: N#CC[C@H](O)c1ccccc1
Temperature: 70 °C

Procedure:
A mixed solvent (volume ratio=1:1, 5 mL) of water and methanol and the iridium aqua complex shown in the following Table 1 (0.5 mol % relative to 2-cyanoacetophenone) were mixed, and 2-cyanoacetophenone (1 mmol) and the hydrogen-donor compound shown in the following Table 1 (5 mmol) were added to the obtained solution at room temperature. The obtained mixture was stirred at 70° C. After confirming the disappearance of 2-cyanoacetophenone by thin layer chromatography, the reaction was quenched with brine (20 mL). The reaction mixture was subjected to extraction treatment (three times) with ethyl acetate (20 mL), and the obtained organic layers were combined. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=20:1) to give (S)-3-phenyl-3-hydroxypropionitrile. The conversion and optical purity are shown in Table 1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[S:28]([O:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CO)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 10 h

Procedure:
To a suspension of (R)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (400 mg, 1.858 mmol) and pyridine (1.10 ml, 13.60 mmol) in tetrahydrofuran (5 ml) was added p-toluenesulfonyl chloride (425 mg, 2.230 mmol) and stirred for 10 hr. To the reaction was added citric acid (4 g) and water (10 mL) and extracted with ethyl acetate (3×10 mL). The organics were combined, dried (MgSO4), filtered, and concentrated. The residue was purified by Analogix® Intelliflash280™ (SiO2, 0-40% ethyl acetate in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13-1.21 (m, 1H) 1.23-1.31 (m, 1H) 1.37 (s, 9H) 1.46-1.55 (m, 1H) 1.59-1.74 (m, 2H) 2.43 (s, 3H) 2.68-2.83 (m, 1H) 3.28-3.32 (m, 1H), 3.67-3.73 (m, 2H) 3.89 (d, J=6.10 Hz, 2H) 7.49 (m, 2H) 7.76-7.81 (m, 2H); MS (DCI) m/z 387 (M+NH4)+.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CN(C)C=O.[CH2:19]([N:26]1[CH2:31][CH2:30][C:29]([OH:32])=[C:28]([C:33](OC)=[O:34])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.CO>[CH2:19]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH:28]([CH2:33][O:34][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C1=C(O)CCN(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
0.82 g of imidazole and 0.72 g of tert-butyldimethylchlorosilane were added to N,N-dimethylformamide (10 mL) solution of 1.0 g of methyl 1-benzyl-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate, and stirred at room temperature for 0.5 hours, and then methanol was added thereto. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water in that order, dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was dissolved in 30 mL of diethyl ether, and with cooling with ice, 0.30 g of lithiumaluminium hydride was added thereto, and stirred at that temperature for 1.5 hours, and then methanol was added thereto. The reaction solution was diluted with ethyl acetate, then washed with water and saturated saline water in that order, dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. High-polarity side products were removed from the resulting residue through silica gel column chromatography (chloroform/methanol=10/1), and the residue was dissolved in 10 mL of N,N-dimethylformamide, and 0.41 g of imidazole and 0.72 g of tert-butyldimethylchlorosilane were added thereto, and stirred at room temperature for 10 minutes. Water was added to the reaction solution, and diluted with ethyl acetate. Then, this was washed with water and saturated saline water in that order, dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=10/1 to 4/1) to obtain 566 mg of the entitled compound as a pale yellow oily substance.
Reaction SMILES: [O:1]=[C:2](CCC1C=CC=CC=1)C(O)=O.C1(CNN)C=CC=CC=1.[Cl:23][C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][C:29]=1[Cl:30].[CH3:37][O-:38].[Na+]>CO>[Cl:23][C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][C:29]=1[Cl:30].[CH3:2][O:1][C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][C:29]=1[O:38][CH3:37].[CH3:2][O:1][C:24]1[N:25]=[N:26][C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:28][C:29]=1[Cl:30]
Reactant: C[O-]
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: Clc1cc(-c2ccccc2)nnc1Cl
Agent: NNCc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ccccc2)nnc1OC
Product: COc1nnc(-c2ccccc2)cc1Cl
Temperature: 65 °C

Procedure:
3,4-Dichloro-6-phenylpyridazine was synthesized from -oxobenzenebutanoic acid and 1-(phenylmethyl)hydrazine in 2 steps according to a procedure by Sircar (Sircar, I. J. Het. Chem. 1983, 20, 1473-1476.) 3,4-Dichloro-6-phenylpyridazine (100 mg, 0.44 mmol) was combined with sodium methoxide (1.1 mL of a 0.50M solution in methanol, 0.55 mmol, 1.25 equiv.) and methanol (296 μl, 1.5M) in a resealable tube and heated to 65° C. for 1 hour. The methanol was evaporated in vacuo, and water was added to the residue. The mixture was extracted with DCM, dried over K2CO3, filtered and concentrated in vacuo, to afford 3,4-dimethoxy-6-phenylpyridazine and 3-methoxy-4-chloro-6-phenylpyridazine, the title compound, as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1I.[N:11]1[CH:16]=[C:15](B(O)O)[CH:14]=[N:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(Cl)Cl>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[C:15]1[CH:16]=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: OB(O)c1cncnc1
Reactant: N#Cc1nccc(I)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#Cc1nccc(-c2cncnc2)c1F
Temperature: 85 °C
Yield: 44.5 %

Procedure:
A vial containing a mixture of 3-fluoro-4-iodopicolinonitrile (3.0 g, 12.10 mmol), pyrimidin-5-ylboronic acid (5.23 g, 42.2 mmol), and cesium carbonate (8.28 g, 25.4 mmol) in dioxane (Ratio: 2.0, Volume: 24.44 ml) and water (Ratio: 1.000, Volume: 12.22 ml) was degassed with N2 for 5 min, then PdCl2(dppf)-CH2Cl2Adduct (0.524 g, 0.641 mmol) was added. The solution was heated at 85° C. for 21 hr, and then allowed to cool to room temperature. The reaction was quenched with water. The reaction mixture was diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a brown residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (120 g column, 85 mL/min, 50-90% EtOAc in hexanes over 25 min, tr=10 min) gave the title compound (1.089 g, 5.39 mmol, 44.5% yield) as an orange solid.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CCOCC>[CH2:1]([CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)NCCc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC(C)(CN)NCCc1ccccc1
Yield: 55.5 %

Procedure:
A solution of 2-benzylmethylamino-2-methyl-propionitrile (6.7 g.) in ether (100 ml.) was added dropwise to a stirred solution of sodium dihydro bis[2-methoxyethoxy] aluminate (28.5 g.) in ether (150 ml.), kept at 0°C. The mixture was then gently refluxed for 20 hrs, and then excess reducing agent was decomposed by the dropwise addition of water to the cooled suspension. The mixture was dried (anhyd.Na2SO4), filtered (hyflo) and the excess ether evaporated under reduced pressure. The residual liquid was distilled under water pump vacuum to give 2-benzylmethylamino-2-methyl-propylamine (3.8 g.) b.p. 138°-140°C.