Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7](=[CH:22][N:23](C)C)[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)=[CH:4][CH:3]=1.[NH2:28]N>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[CH:22]=[N:23][NH:28][C:8]=2[C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CN(C)C=C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1[nH]ncc1Cc1ccc(Cl)cc1
Temperature: 70 °C
Yield: 66.3 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-(4-chlorobenzyl)-3-(dimethylamino)acryloyl)pyrrolidine-1-carboxylate (580 mg, 1.5 mmol) in ethanol (10 mL) was added hydrazine (480 mg, 15 mmol). The resulting solution was heated at 70° C. for 2 h and concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-tert-butyl 2-(4-(4-chlorobenzyl)-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (360 mg, 67%). LCMS: calculated: 365, found (MH+): 366.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Cc1ccccc1)OCC
Yield: 43.2 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055 mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) was stirred with acetic acid (15.7 μL, 0.28 mmol) in DMF (0.5 mL) at room temperature over night. The reaction was quenched with a 10% aqueous Na2CO3 solution and the product was extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. The product was purified purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product (43%) as a clear gel. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H), 1.24 (t, 6H, J=7 Hz), 1.86 (s, 3H), 1.88-2.02 (m, 2H), 2.16 (s, 3H), 2.65-2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J=7 Hz), 3.76 (s, 3H), 4.00 (pent, 4H, J=7 Hz), 4.25-4.34 (m, 2H), 5.11 (s, 2H), 5.34-5.43 (m, 1H), 7.18-7.33 (m, 5H) ppm; 31P (121.4 MHz, CDCl3) δ 30.9 ppm; MS (m/z) 632.4 [M+H]+, 654.3 [M+Na]+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(Cl)Cl>CN(C=O)C>[CH2:37]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:8]1[C:20]1[N:21]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:22]([Br:26])=[C:23]([Br:25])[N:24]=1)[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3nc(Br)c(Br)n3COCC[Si](C)(C)C)[nH]c2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCn1c(-c2nc(Br)c(Br)n2COCC[Si](C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-cyclohexyl-2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1H-indole-6-carboxylate (428 mg, 0.7 mmol) in dry DMF (5 mL) was added KH (30% in oil, 0.8 mmol, 109 mg) proportion-wise at RT. The mixture was stirred at RT for 10 min until no further effervescence was observed. Allyl bromide (420 mg, 3.5 mmol) was added and the resulting mixture was stirred at RT for 15 min. Methylene chloride (10 mL) was added and the solution was washed with 1N HCl (3×10 mL), dried (Na2SO4), filtered and evaporated to give the title compound in a form pure enough for use in the following step (100%). 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 0.80 (m, 2H), 1.00–2.00(m, 10H), 2.45 (m, 1H), 3.43 (dd, 2H, J=7.5, 9.6 Hz), 3.91 (s, 3H), 4.50 (dd, 1H, J=4.8, 15.0), 4.60 (dd, 1H, J=6.0, 15.0), 4.88 (dd, 1H, J=1.2, 17.1 Hz), 5.03 (s, 2H), 5.04 (dd, 1H, J=0.9, 9.0 Hz), 5.78 (m, 1H), 7.75 (dd, 1H, J=1.5, 8.5 Hz), 7.82 (d, 1H, J=8.5 Hz), 8.02 (s, 1H).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:20](=[O:22])[CH3:21])=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: NCCOc1ccc(Br)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-((6-bromopyridin-3-yl)oxy)ethanamine dihydrochloride obtained in Reference Example 5 (1.00 g), pyridine (1.12 mL) and tetrahydrofuran (20 mL) was added dropwise acetyl chloride (0.368 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 hr, aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration, and washed with diisopropyl ether to give the title compound (0.792 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[O:20][CH3:19])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1CNc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-phenyl-quinolin-2-ylamine (CAS 51478-40-1, 750 mg, 2.94 mmol) was dissolved in 40 mL dichloromethane. 2-Methoxybenzaldehyde (481 mg, 3.54 mmol) and acetic acid (354 mg, 5.9 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. Sodium triacetoxy borohydride (1.39 g, 6.59 mmol) was added and stirring was continued overnight. The reaction mixture was quenched by addition of 100 mL sat. sodiumbicarbonate solution. The mixture was extracted three times with dichloromethane (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (6-Chloro-4-phenyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as an off-white solid (595 mg, 54%), MS: m/e=375.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].O(CC)[C:12]([S-])=[S:13].[K+]>C(O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:12]([SH:13])[O:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(N)c(O)c1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc2nc(S)oc2c1
Yield: 79.3 %

Procedure:
Next, a mixture of 2-amino-5-methoxyphenol (3c) (6.03 g, 43.33 mmol) and potassium ethyl xanthate (6.95 g, 73.33 mmol) in ethanol (80 mL) was heated at reflux for 18 h. The reaction was subsequently cooled and the solvent was removed in vacuo. The residue was taken up in ethyl acetate (150 mL), washed successively with 4N HCl, water, and brine. The organic solution was subsequently dried over Na2SO4. After filtration to remove the drying aid, the solvent was evaporated to give 6.23 g (79%) of 6-methoxybenzoxazole-2-thiol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[O:10]N.O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>>[Cl:2][C:3]1[C:4]2[O:10][C:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]=3[C:5]=2[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: NOc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Br)cc3c2C1
Yield: 20 %

Procedure:
The product of step A was reacted with tert-butyl 4-oxopiperidine-1-carboxylate then Boc protected following the procedure of Example 29, step B. Purification by flash column chromatography (SiO2, 95:5 hexanes/ethyl acetate) provided tert-butyl 6-chloro-8-bromo-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (3.9 g, 20%) as a pink solid: 1H NMR (CDCl3, 300 MHz) δ 7.44 (d, J=1.5 Hz, 1H), 7.38 (d, J=1.5 Hz, 1H), 4.50 (s, 2H), 3.88 (t, J=5.4 Hz, 2H), 2.89 (t, J=5.4 Hz, 2H), 1.49 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([N:37]7[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]7)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Reactant: C1CNCCN1
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(N4CCNCC4)ncc3Cl)cc1-2
Reaction time: 24 h
Yield: 55.6 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 211 (1 g, 0.0018 mol) and piperazine (3 g, 0.036 mol) in EtOH (4 mL). The reaction was run at 95° C. for 24 h. After allowing the reaction mixture to cool down, the volatiles were removed under vacuum. The residue was triturated with H2O and finally with EtOH to yield 0.572 g of the title compound (yield: 55%). 1H NMR (300 MHz, d6-DMSO): δ 2.71 (s, broad, 4H), 2.86–3.30 (m, 4H), 3.39 (s, broad, 4H), 6.07 (s, 2H), 6.85 (s, 1H), 6.93–6.95 (dd, 1H, J=8.2 Hz, 1.9 Hz), 7.00 (d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=1.9 Hz), 7.24–7.30 (m, 3H), 7.38–7.41 (dd, 1H, J=8.2 Hz, 1.74 Hz), 7.49 (s, 1H), 8.12 (s, 1H), 10.32 (s, 1H). M+1=573.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CCCC1
Reactant: OB(O)c1ccccc1
Product: O=C1CCCC(c2ccccc2)C1

Procedure:
The title compound was obtained using a procedure analogous to that described in Step 1 of Example 10 using cyclohex-2-enone (1.0 g, 10.4 mmol) and phenylboronic acid (1.3 g, 10.4 mmol) to afford the title compound as a colorless oil. MS m/z: 175(M+1).
Reaction SMILES: O([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])S(C(F)(F)F)(=O)=O.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH3:39])[C:25]=1[C:26]1[C:31]([CH3:32])=[CH:30][C:29]([CH:33]([C:36]#[N:37])[C:34]#[N:35])=[CH:28][C:27]=1[CH3:38].C[O-].[Na+]>C(Cl)Cl.CO>[CH3:19][C:20]1[C:25](=[C:26]2[C:31]([CH3:32])=[CH:30][C:29](=[C:33]([C:34]#[N:35])[C:36]#[N:37])[CH:28]=[C:27]2[CH3:38])[C:24]([CH3:39])=[CH:23][N:22]([CH2:9][CH:10]([CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:21]=1
Reactant: CCCCCC(CCC)COS(=O)(=O)C(F)(F)F
Reactant: Cc1cncc(C)c1-c1c(C)cc(C(C#N)C#N)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCC(CCC)CN1C=C(C)C(=c2c(C)cc(=C(C#N)C#N)cc2C)C(C)=C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
To a solution of 2-propyl-1-heptanol (0.81 g, 5.1 mmol) in dry CH2Cl2 (15 mL) was added dropwise a solution of trifluoromethanesulfonic anhydride (1.77 g, 6.10 mmol) in the same solvent (5 mL). After stirring at room temperature for 20 min, the reaction mixture was poured into ice (40 mL) and neutralized with saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to yield nearly pure 2-propyl-1-heptyl triflate as a purple liquid (1.40 g, 94.1%). The 2-propyl-1-heptyl triflate (0.319 g, 1.10 mmol) was next added dropwise to a solution of 15 (0.275 g, 1.00 mmol) in dry CH2Cl2 (10 mL), and the reaction mixture was stirred at room temperature for 12 h. A solution of sodium methoxide in methanol (2.4 mL, 0.5 M) was then added dropwise to the resulting solution of pyridinium salt 17. The color of the mixture immediately changed from yellow to purple. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting purple solid was then partitioned between water (20 mL) and CH2Cl2 (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was next purified by flash chromatography on silica gel eluting with 4:100 methanol: CH2Cl2, to give 0.278 g (66.9%) of the title compound as an orange solid: mp 276-278° C.; 1H NMR (400 MHz, DMSO-d6): δ 8.969 (s, 2H), 6.591 (s, 2H), 4.421 (t, 2H, J=5.6 Hz), 2.114 (m, 1H), 2.067 (s, 6H), 1.704 (s, 6H), 1.229-1.190 (m, 12H), 0.836 (m, 6H); 13C NMR (125 MHz, DMSO-d6): δ 159.170, 142.273, 142.082, 137.669, 132.328, 125.659, 122.083, 117.561, 63.995, 38.500, 32.713, 31.339, 30.165, 27.600, 25.025, 21.849, 19.165, 18.846, 16.653, 14.188, 13.897; MS (high resolution, EI): m/z 415.2985 [M+]; calcd, 415.2987; Anal. Calcd. for C28H37N3.1/3H2O: C, 79.76; H, 9.00; N, 9.97. Found; C, 79.92; H, 8.87; N, 9.97.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](I)=[CH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH2:16])[CH:18]=[CH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C=C(I)c1ccc(OCc2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CC(=C)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-benzyloxy-4-(1-iodo-vinyl)-benzene (12.0 g, 0.035 mol), vinyl tributyl tin (16.0 mL, 0.056 mol) and PdCl2(CH3CN)2 (150 mg, 0.0579 mmol) were dissolved in DMF (300 mL). The reaction mixture was stirred at 25° C. for 16 h, then partitioned between ethyl acetate (800 mL) and H2O (400 mL). The organic layer was washed by brine, concentrated and purified on SiO2 (15% ethyl acetate/Hexane) to yield 1-benzyloxy-4-(1-methylene-allyl)-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=Cc1cnc2ccc(Cl)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-3-carbaldehyde (0.55 g, 3 mmol) in methanol (20 mL) was added sodium borohydride (0.15 g, 4 mmol) in a small portions at rt. After stirring at rt for 30 min, the reaction was quenched with water, and extracted with DCM to give crude product (0.55 g, 100% yield). 40 mg of crude product was purified by Prep HPLC to give (6-chloroimidazo[1,2-b]pyridazin-3-yl)methanol as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.95 (d, J=9.35 Hz, 1H), 7.79 (s, 1H), 7.11 (d, J=9.35 Hz, 1H), 5.07 (s, 2H); LRMS (ESI) m/e 184.0 [(M+H)+, calcd for C7H7ClN3O 184.6].
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:14][C:12]1[CH:11]=[CH:10][C:9]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccc(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Temperature: 35 °C

Procedure:
A suspension of (trimethylsilyl)acetylene (0.696 g, 7.08 mmol), methyl 2-(2-bromo-4-fluorophenyl)acetate (A48) (0.500 g, 2.02 mmol), PPh3 (0.053 g, 0.202 mmol), CuI (39 mg, 0.202 mmol), Et3N (1.41 mL, 10.1 mmol) and PdCl2(PPh3)2 (0.142 g, 0.202 mmol) in THF (25 mL) was heated at 35° C. for 16 hours. The resulting mixture was adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound A49 as a clear oil (0.212 g, 40%); LCMS-A: rt 6.830 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28]C)=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[OH:39][C:33]([C:35]([F:38])([F:37])[F:36])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[OH:28])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1

Procedure:
The solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (2.247 g, 5.26 mmol) in mixed solvent of DCM/TFA (24 mL, 3:1, v/v) was stirred at rt for 30 min. The solvents were removed in vacuo to produce 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate TFA salt in quantitative yield. MS ESI +ve m/z 327 (M+H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:34])([F:33])[F:32])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:31]([F:33])([F:32])[F:34])[O:15][N:14]=[C:13]([C:16]3[CH:29]=[CH:28][C:19]([C:20]([N:22]([CH:23]4[CH2:27][CH2:26][CH2:25][O:24]4)[C:36](=[O:37])[O:38][CH3:39])=[O:21])=[C:18]([CH3:30])[CH:17]=3)[CH2:12]2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CCCO1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C1CCCO1
Yield: 23.7 %

Procedure:
In a suspension of 0.07 g of 55% oily sodium hydride in 10 mL of tetrahydrofuran, a solution of 0.49 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(2-tetrahydrofuranyl)benzoic acid amide in 5 mL of tetrahydrofuran was added dropwise under cooling with ice and with stirring. After the completion of the addition dropwise, it was stirred at at room temperature for 10 minutes. Then, 0.15 g of methyl chloroformate was added, and continued to stir at the same temperature further for 15 hours. After the completion of the reaction, the reaction was poured in 10 mL of water, extracted with ethyl acetate (20 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.13 g of the aimed product as colorless resinous substance.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:10](OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>O1CCOCC1>[CH3:10][NH:9][CH2:8][CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: NCCC1=CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CNCCC1=CCCCC1
Reaction time: 3 h
Yield: 18 %

Procedure:
To a solution of 2-(1-cyclohexenyl)ethylamine (4.0 g) in 1,4-dioxane (40 mL) was added di-tert-butyldicarbonate (7.7 g). After gas evolution ceased (≈2 h) the reaction was concentrated. A portion of the residue (2 g) was dissolved in THF (10 mL) followed by addition of LiAlH4 (10 mL, 1M THF), which caused an exotherm. After 3 h, more LiAlH4 solution was added (4 mL), and the reaction was warmed to reflux. After 1 h, the reaction was cooled, and quenched cautiously with vigorous stirring by the addition of water (0.57 mL), 1M NaOH (0.6 mL), and more water (1.5 mL). The suspension was filtered through celite, which was washed with ether. The organic solution was concentrated to give the desired product as a volatile oil (0.8 g).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[H-].[Na+].[CH2:12](Br)[CH:13]=[CH2:14]>CN(C=O)C.CCOCC>[CH2:14]([O:9][C:3]1([C:1]#[CH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH:13]=[CH2:12]
Reactant: C#CC1(O)CCCCC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC1(OCC=C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of 1-ethynylcyclohexanol (2.28 g, 18.36 mmol) in DMF (25 ml) was cooled (0° C. ice bath) and treated with 60% NaH (0.890 g, 22.25 mmol). The reaction was stirred for 30 min, then warmed to room temperature and stirred for 1 hr. To this was added allyl bromide (4.8 ml, 55.5 mmol) over 5 min and continued stirring for 16 h. The reaction was diluted with Et2O (75 mL), washed with water (4×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to give the product, 1-(allyloxy)-1-ethynylcyclohexane (2.873 g, 12.24 mmol, 66.7% yield) as a pale yellow mobile oil. 1H NMR consistent with expected product, consists of approx 3:1 product/SM. Used as-is without further purification 1H NMR (CDCl3) δ: 5.94-6.04 (m, 1H), 5.33 (dq, J=17.2, 1.7 Hz, 1H), 5.17 (dq, J=10.3, 1.5 Hz, 1H), 4.15 (dt, J=5.6, 1.5 Hz, 2H), 2.50 (s, 1H), 2.49 (s, 1H), 1.91-1.98 (m, 3H), 1.49-1.77 (m, 12H), 1.24-1.38 (m, 3H).