Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1
Reactant: Nc1cccc(I)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CNc1cccc(I)c1
Yield: 150.5 %

Procedure:
A mixture of 3-iodoaniline (40.0 g), methyl chloroacetate (37.12 g) and sodium bicarbonate (30.75 g) was heated in acetonitrile (400 ml) at reflux for 2 days under nitrogen. Ethyl acetate (250 ml) was then added and the mixture was washed with water (2×250 ml) dried and evaporated to give an oil (ca. 80 g), a sample of which (1.2 g) was purified by FCC eluting with ether-petroleum ether (7-3) to give the title compound (Intermediate 27; 0.8 g) as a solid, m.p. 83°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[N:15]O)[NH2:14])=[C:11]([CH3:19])[CH:10]=1>N1CCCCC1>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[NH:15][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][N:14]=2)=[C:11]([CH3:19])[CH:10]=1
Reactant: Cc1cc(Cl)ccc1C(N)=NO
Reactant: O=Cc1ccco1
Solvent: C1CCNCC1
Product: Cc1cc(Cl)ccc1C1=NOC(c2ccco2)N1
Temperature: 10 °C
Yield: 18.1 %

Procedure:
A mixture of 2-furancarboxaldehyde (166 mL, 192 mg, 2.0 mmol), 4-chloro-N′-hydroxy-2-methylbenzimidamide (368 mg, 2.0 mmol) and one drop of piperidine was heated to 10° C. for 4 h. The mixture was cooled to room temperature and purified by automated column chromatography on the ISCO COMPANION (SiO2, gradient heptanes/ethyl acetate) to give the 3-(4-chloro-2-methylphenyl)-5-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product (95 mg) with a yield of 18%. LC-MS [M+H] 263 (C13H11ClN2O2+H, expected 263.05)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CCC1
Reactant: OB(O)Oc1ccc(OCc2ccccc2)cc1
Product: O=C1CC[C@@H](c2ccc(OCc3ccccc3)cc2)C1
Yield: 63.7 %

Procedure:
4-Benzyloxyphenylboric acid (15.1 g, 66 mmol) and cyclopentenone (2.5 mL, 30 mmol) were used and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (5.09 g, 64%).
Reaction SMILES: [OH-].[K+].[I-].[NH2:4][N+:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O.ClCCl>[F:11][C:12]([F:20])([F:21])[C:13]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: N[n+]1ccccc1
Reactant: CCOC(=O)C#CC(F)(F)F
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(C(F)(F)F)nn2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
A mixture of 2.1 g (37.6 mmol) of potassium hydroxide and 6.7 g (30.1 mmol) of aminopyridinium iodide in 20 ml of water is added to a solution of 2.5 g (15.1 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in 25 ml of dichloromethane. After stirring for 5 h at ambient temperature, water is added and the mixture is extracted with dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated to dryness. The crude product is purified by chromatography over silica gel eluted with an 80/20 heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl 2-trifluoromethylpyrazolo[1,5-a]pyridine-3-carboxylate are obtained in the form of a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([O:22][CH3:23])=[N:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:40][NH:41]2)C1C=CC=CC=1)C>>[CH3:23][O:22][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([NH:41][CH3:40])=[O:3])[NH:17][N:16]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]nc(OC)c12
Product: CNC(=O)C=C(c1ccccc1)c1cccc2[nH]nc(OC)c12

Procedure:
3-(3-Methoxy-1H-indazol-4-yl)-N-methyl-3-phenyl-acrylamide CLXXXVIII was prepared from 3-(3-methoxy-1H-indazol-4-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:40](=[O:41])[CH2:39][C:33]3([CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:32][C:31]=2OC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)#[N:8]>CN(C)C=O>[O:18]=[C:17]1[NH:16][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)[C:30]2[C:40](=[O:41])[CH2:39][C:33]3([CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:32][C:31]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1
Reactant: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC2(CCOCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC2(CCOCC2)C3)cc1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (49 mg, 0.44 mmol) is added to a solution of 1-((4-cyanophenyl)-(8-methoxy-10-oxo-3-oxaspiro[5.5]undec-8-en-9-yl)methyl)-3-(3-(trifluoromethyl)phenyl) urea (intermediate 11, 224 mg, 0.44 mmol) in N,N-dimethylformamide (3 mL). The mixture is stirred at room temperature over night and then purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 21 mg; ESI mass spectrum [M+H]+=482, Retention time HPLC: 1.04 min (V011_S01).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])=[CH:17][C:16]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[O:14].S(=NC(N)=O)(=O)=O>>[Cl:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:1][C:31]([NH:30][S:27]([C:16]2[CH:17]=[C:18]([N:21]([C:23]([O:25][CH3:26])=[O:24])[CH3:22])[CH:19]=[CH:20][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:28])=[O:29])=[O:32])[N:7]=1
Reactant: COc1cc(Cl)nc(N)n1
Reactant: COC(=O)c1ccc(N(C)C(=O)OC)cc1S(=O)(=O)N=C=O
Agent: NC(=O)N=S(=O)=O
Product: COC(=O)c1ccc(N(C)C(=O)OC)cc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1

Procedure:
By analogy with Example m), 0.9 g of 2-amino-4-chloro-6-methoxypyrimidine is reacted with 2.1 g of 2-methoxycarbonyl-5-(N-methoxycarbonyl-N-methylamino)benzenesulfonyl isocyanate (Example 1)). Yield: 0.45 g of the desired sulfonylurea as a solid foam:
Reaction SMILES: C=O.[C:3]([BH3-])#[N:4].[Na+].FC(F)(F)C(O)=O.[C:14]1([S:20]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=3)[C:25]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH:42]4[CH2:46][CH2:45]N[CH2:43]4)=[C:38]([CH3:47])[CH:37]=3)(=[O:35])=[O:34])=[CH:24]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C>[C:14]1([S:20]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=3)[C:25]([S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH:42]4[CH2:46][CH2:45][N:4]([CH3:3])[CH2:43]4)=[C:38]([CH3:47])[CH:37]=3)(=[O:34])=[O:35])=[CH:24]2)(=[O:21])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [BH3-]C#N
Reactant: Cc1cc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)ccc1C1CCNC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)ccc1C1CCN(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Formaldehyde (37% in water, 0.19 mL, 2.505 mmol) and sodium cyanoborohydride (63 mg, 1.002 mmol) were added to a solution of 1-benzenesulfonyl-5-fluoro-3-(3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl)-1H-indole trifluoroacetate (0.305 mg, 0.5011 mmol) in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 2 hours, then buffered to pH 12 by addition of 1 M aqueous NaOH. The mixture was extracted with DCM, and the combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (DCM/MeOH(NH4OH) to give 0.209 g (81% yield) of 1-benzenesulfonyl-5-fluoro-3-[3-methyl-4-(1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-1H-indole as a white foam. MS (M+H)=513.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:16])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:44]=[C:45]=[O:46])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>N1C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:16])[CH2:12][O:13][C:45](=[O:46])[NH:44][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(CO)COC(=O)c1ccccc1)OC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)c1ccccc1)CC(C)OC(=O)c1ccccc1
Temperature: 70 °C
Yield: 91.1 %

Procedure:
A mixture of 3.70 g (11.2 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hydroxypropyl benzoate m5 and 4.964 g (16.8 mM) of octadecyl isocyanate in 74 ml of pyridine is heated at 70° C. for 15 hours and the solvent is evaporated. To the residue with cooling, is added 2N aqueous hydrochloric acid and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the product by column silica gel chromatography using n-hexane-ethyl acetate (1:1) as an eluent gives 6.28 g (87.8% yield) of the titled compound m6.
Reaction SMILES: C([Sn](CCCC)(CCCC)OC)CCC.Br[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH3:25].C([O:29][C:30]([CH3:32])=[CH2:31])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[F-].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:31][C:30](=[O:29])[CH3:32])=[C:18]([CH3:25])[CH:19]=1
Reactant: COc1ccc(Br)c(C)c1
Reactant: C=C(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn](CCCC)(CCCC)OC
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This experiment was carried out four times. Tributyl(methoxy)stannane (400 g, 1.24 mol), 1-bromo-4-methoxy-2-methylbenzene (250 g, 1.24 mol), prop-1-en-2-yl acetate (187 g, 1.87 mol), palladium(II) acetate (7.5 g, 33 mmol) and tri-o-tolylphosphine (10 g, 33 mmol) were stirred together in toluene (2 L) at 100° C. for 18 hours. After it had cooled to room temperature, the reaction mixture was treated with aqueous potassium fluoride solution (4 M, 400 mL) and stirred for 2 hours at 40° C. The resulting mixture was diluted with toluene (500 mL) and filtered through diatomaceous earth; the filter pad was thoroughly washed with ethyl acetate (2×1.5 L). The organic phase from the combined filtrates was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether) provided the product as a yellow oil. Combined yield: 602 g, 3.38 mol, 68%. LCMS m/z 179.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.05 (d, J=8.3 Hz, 1H), 6.70-6.77 (m, 2H), 3.79 (s, 3H), 3.65 (s, 2H), 2.22 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[C:31]([NH:36]N)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: NNc1cccc2ncccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]=[CH2:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].[C:14]1(O)C=CC=CC=1.IC>ClC1C=CC=CC=1Cl.CO.[OH-].[Na+].O>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH:2]=[CH2:3])[C:5]=1[O:13][CH3:14])[CH:11]=[CH2:12]
Reactant: C=CCc1cccc(CC=C)c1O
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CI
Solvent: O
Product: C=CCc1cccc(CC=C)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Diallylphenol was prepared via reacting 2-allylphenol with an allyl halide to form 2-allylphenyl ether. Refluxing the latter in o-dichlorobenzene for 24–48 hrs. gave 2,6-diallylphenol. The desired phenol was purified by distillation, bp 91–92 C(1 mm). MS m/z 174 (M+ calcd for C12H14O=174). H NMR (300 MHz, CDCl3), d 3.48 (d, 4, CH2), 5.15–5.38 (m, 4,vinyl), 5.98–6.18 (m, 2, CH vinyl), 6.85–7.15 (m, 3 aromatic). 2,6-Diallylphenol (5.2 g, 0.03 mol) was diluted with methanol (50 ml) and sodium hydroxide added to the phenol solution. Iodomethane (5.0 g, 0.03 mol.) was added to the solution and stirred overnight at room temperature. The methanol solution was diluted with water and the product extracted with hexane, dried over MgSO4, filtered and evaporated to give 2,6-diallylanisole. MS m/z 188 (M+ calcd for C13H16O=188). H NMR (300 MHz, CDCl3) d 3.45–3.55 (d, 4, CH2), 3.60 (s, 3, CH3), 5.10–5.20 (d, 4, CH2), 6.00–6.16 (m, 2, CH vinyl), 7.07–7.20 (m, 3, aromatic). 2,6-Diallylanisole was oxidized with meta-chloro perbenzoic acid as follows: MCPBA (˜70%, 5.73 g) was dissolved in dichloromethane (50 ml) and dried over MgSO4. After filtration of the MgSO4, 2,6-diallylanisole (1.88 g, 0.01 mol) was added to the MCPBA solution and stirred for 24–48 hrs. at room temperature. The precipitate, m-chlorobenzoic acid was filtered and, the dichloromethane solution washed with dilute sodium bisulfite and dilute potassium carbonate and dried over MgSO4. After filtration of the MgSO4, the dichloromethane was evaporated to give the liquid diepoxide, bp 138° C. (1 mm). MS m/z 220 (M+ calcd for C13H16O3=220). H NMR (300 MHz, CDCL3) d 2.60–2.70 (m, 2, CH2 epoxypropyl), 2.75–3.10 (m, 6, CH2 epoxypropyl), 3.25–3.50 (m, 2, CH epoxypropyl), 3.82 (s, 3, OCH3), 7.05–7.25 (m, 1, aromatic), 7.40–7.60 (m, 2, aromatic).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH3:17])[C:14]=2[CH3:16])[CH2:9][C:8]2([CH2:22][CH2:21][CH2:20]2)[CH2:7]1)=[N+]=[N-].C(OC(=O)C)C>CO.[Pd]>[CH3:19][O:18][C:12]1[CH:11]=[C:10]2[C:15](=[C:14]([CH3:16])[C:13]=1[CH3:17])[N:6]([CH2:5][CH2:4][NH2:1])[CH2:7][C:8]1([CH2:20][CH2:21][CH2:22]1)[CH2:9]2
Reactant: COc1cc2c(c(C)c1C)N(CCN=[N+]=[N-])CC1(CCC1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(c(C)c1C)N(CCN)CC1(CCC1)C2
Reaction time: 1 h
Yield: 89.5 %

Procedure:
A solution of 6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (1.12 g), 1,2-dibromoethane (2 mL) and Cs2CO3 (3.16 9) in DMF (7 mL) was heated in a bath of 110° C. for 6 hours. The mixture was cooled, water was added, and extracted with dichloromethane. The organic phase was then washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.6) to give 1′-(2-bromoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] which was then added NaN3 (1.1 g) and dissolved in dichloromethane (7 mL). After heating the solution in a bath of 90° C. for 1 hour, the mixture was cooled, mixed with water and extracted with dichloromethane. The organic phase was washed with brine, dried and evaporated. The residue was passed through a column (Hexane/EtOAc, 10:0.5-10:0.6) to give 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) as an oil. 1′-(2-azidoethyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (340 mg) was dissolved in methanol (7 mL) and ethylacetate to which 50 mg Pd/C (10%) was added. The flask was then flushed evacuated and flushed with hydrogen. Under a balloon of hydrogen for 1 hour, the mixture was filtered and evaporated to give 2-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)ethanamine (278 mg) as an oil. 1H-NMR (300 MHz, C2D6O) δ=6.414 (s, 1H); 3.77 (s, 3H); 3.52 (s, 2H); 3.16-2.92 (m, 4H); 2.81 (s, 2H); 2.18 (s, 3H); 2.12 (s, 3H); 2.03-1.86 (m, 4H); 1.84-1.64 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1.CCN(CC)CC.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][NH:16][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1
Reactant: NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155.3 %

Procedure:
To a mixture of 2-(2-(4,5-dichloro-2-iodophenoxy)pyridin-4-yloxy)ethanamine (30 mg, 0.07 mmol), Et3N (35.7 mg, 0.35 mmol) in DCM (5 mL), 2-chloroethanesulfonyl chloride (11.5 mg, 0.07 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. Then solvent was removed under reduced pressure. The residue was taken in THF (2 mL) and H2O (2 mL), then K2CO3 (100 mg) was added and the resulting mixture was stirred at room temperature for 1 h. The mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (DCM/ethyl acetate=5:1) to afford the desired product (56 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ: 7.98 (d, J=5.6 Hz, 1H), 7.92 (s, 1H), 7.25 (s, 1H), 6.61-6.57 (m, 2H), 6.47 (d, J=2.0 Hz, 1H), 6.32 (d, J=16.4 Hz, 1H), 6.00 (d, J=10.0 Hz, 1H), 4.77 (t, J=5.2 Hz, 1H), 4.18 (t, J=5.2 Hz, 2H), 3.51-3.47 (m, 2H). ESI-MS m/z: 515.0[M+H]+.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O-:18])=[O:17])[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)[CH3:2].[CH2:19](I)[CH3:20]>>[CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)[O-])CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCI
Product: CCOC(=O)C1(CC)CCCN(C(=O)OC(C)(C)C)C1

Procedure:
The target was synthesized as in Production Example 11(1), using 1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate and ethyl iodide as the raw material.
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[O:18]=[O+][O-].CSC>C(Cl)Cl>[N:16]1[C:17]2[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[O+][O-]
Reactant: C(=C1CCCc2cccnc21)c1ccccc1
Solvent: CSC
Solvent: ClCCl
Product: O=C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 8-benzylidene-5,6,7,8-tetrahydro-quinoline (4.30 g, 19.4 mmole) in CH2Cl2 (150 mL) was reacted with ozone at −78° C. for 30 minutes. Dimethyl sulfide (5 mL) was added, and the reaction was warmed to RT and stirred overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc). The title compound (2.20 g, 79%) was obtained as an off-white solid after drying in vacuo: MS (ES) m/e 148 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:14])([F:13])[C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[C:1](=[O:2])=[N:12][C:10]1[S:11][C:7]([C:6]([F:14])([F:13])[F:5])=[N:8][N:9]=1.[C:1](=[O:2])=[N:12][C:10]1[S:11][C:7]([C:6]([F:14])([F:13])[F:5])=[N:8][N:9]=1
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C(F)(F)F)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-trifluoromethyl-2-amino-1,3,4-thiadiazole (45 grams) in ethyl acetate (300 ml) was added to the reaction vessel, and the resulting mixture was stirred for a period of about 16 hours resulting in the formation of precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was filtered to recover 48 grams of a white solid. This solid was recrystallized from dimethyl formamide to yield the desired product 5-trifluoromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=3[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:18]2[C:19]([F:21])=[C:20]3[C:15]([C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12][N:11]3[CH:8]3[CH2:10][CH2:9]3)=[CH:16][C:17]=2[F:23])[CH2:3]1
Reactant: N[C@H]1CCCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N[C@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 79.9 %

Procedure:
A suspension of (S)-3-aminopiperidine (4.0 g) obtained as described in the step (c) above 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(11.4 g) and triethylamine (8.4 g) in acetonitrile (250 ml) was refluxed for 3 hours with stirring. Then the mixture was cooled down and filtrationof the precipitated powder followed by treatment with a mixture of ethanol (550 ml) and water (250 ml) gave (S)-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.6 g) as colorless needles. m.p. 247.8° C. (decomposition).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[C:14]([CH2:15][O:16][C:17]3[C:22]([CH:23]=[O:24])=[CH:21][C:20]([O:25]C)=[N:19][CH:18]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.[OH-].[Na+]>O>[O:25]=[C:20]1[CH:21]=[C:22]([CH:23]=[O:24])[C:17]([O:16][CH2:15][C:14]2[C:9]([C:8]3[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:18][NH:19]1
Reactant: COc1cc(C=O)c(OCc2cccnc2-c2ccnn2C(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1nccc1-c1ncccc1COc1c[nH]c(=O)cc1C=O
Reaction time: 20 h

Procedure:
To 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (590 mg) suspended in water (5.0 mL) was added HCl (6 N, 4 mL). Once the mixture turned into a homogeneous solution, it was freeze at −78° C. to an solid and pump under high vacuum 0/N. The yellow solid was continued to pump at 45° C. for 20 h, dissolved in water (2.0 mL), and basified to pH 11 with NaOH (2 N). The aqueous layer was washed with DCM three times and the pH of the mixture was adjusted to pH 6-7. The solid was collected and dried to give 2-oxo-5-[[2-(2-propan-2-ylpyrazol-3-yl)pyridin-3-yl]methoxy]-1H-pyridine-4-carbaldehyde as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 8.8 (dd, J=4.7, 1.6 Hz, 1H), 8.1 (dd, J=7.9, 1.5 Hz, 1H), 7.6 (s, 1H), 7.5 (d, J=1.8 Hz, 1H), 7.1 (s, 1H), 7.0 (s, 1H), 6.6 (d, J=1.8 Hz, 1H), 4.9 (s, 2H), 4.7 (sep, J=6.6 Hz, 1H), 1.5 (d, J=6.6 Hz, 6H); MS (ESI) m/z 339.4 [M+H]+.