Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10](S(C)(=O)=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[CH:28][O:29][CH2:30][F:31])[C:24]([O:26][CH3:27])=[O:25].[H-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[N:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[CH:28][O:29][CH2:30][F:31])[C:24]([O:26][CH3:27])=[O:25])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(=COCF)c1ccccc1O
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)ns1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=COCF)c1ccccc1Oc1nc(-c2ccccc2)ns1
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A solution of 3.2 g (0.005 mol) of 3-phenyl-5-methanesulphonyl-1,2,4-thiadiazole and 2.3 g of methyl 2-(2-hydroxyphenyl)-3-fluoromethoxy-acrylate in 10 ml of dry dimethylformamide is treated at 0° C. with 0.2 g (0.005 mol) of 80% strength sodium hydride in mineral oil. The mixture is stirred for 4 hours at this temperature, and for a further 18 hours without cooling, and then concentrated. The residue is taken up using ethyl acetate, the solution is washed with water, and the organic phase is dried over sodium sulphate and concentrated again. The crude product is chromatographed on silica gel using hexane/acetone (7:3). 1.3 g (67% of theory) of methyl 2-[2-(3-phenyl-1,2,4-thiadiazol-5-yloxy)-phenyl]-3-fluoromethoxy-acrylate are obtained as a yellow, highly viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11](Cl)=[O:12])[N:10]=2)[N:7]=1.[N-:14]=[N+:15]=[N-:16].[Na+].C([O-])(O)=O.[Na+]>CC(C)=O>[N:14]([C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:12])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine-2-carbonyl chloride from Step 1 (2.2 g, 10 mmol) in acetone (40 mL) was added sodium azide (0.43 g, 6.6 mmol, solution in 1.5 mL H2O). The mixture was stirred at 25° C. for 1 h then poured into aq. NaHCO3. The solid precipitate was collected by careful filtration. The filtercake was not allowed to go dry (solvent-free). The filtercake was washed with benzene (2×50 mL) and then transferred to a 150-mL, round-bottomed flask. To azeotropically remove residual water, the solid was suspended in benzene (75 mL) and then concentrated to one-third its volume. Then once again the material was suspended in benzene (75 mL) and concentrated to near dryness to provide the title compound, which was taken on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24](=[O:25])[CH2:23][O:22][CH3:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 99.9 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-methoxyacetyl chloride (0.43 g, 4.0 mmol). The stirred mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.69 g (100%) of product as an off-white solid: mp 246-248° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 10.30 (s, 1H), 8.70 (d, J=8.4 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 5.17 (dd, J=5.2 and 12.7 Hz, 1H), 4.11 (s, 2H), 3.49 (s, 3H), 2.98-2.84 (m, 1H), 2.66-2.47 (m, 2H), 2.12-2.07 (m, 1H); 13C NMR (DMSO-d6) δ 172.67, 169.66, 169.02, 168.25, 166.61, 136.48, 135.91, 131.24, 124.35, 118.31, 116.04, 71.40, 59.10, 48.96, 30.91, 21.94; Anal. Calcd. For C16H15N3O6: C, 55.65; H, 4.38; N, 12.17. Found: C, 55.58; H, 4.40; N, 12.08.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(F)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O>C(O)C>[CH3:2][C:1]1[S:3][CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cs1
Yield: 2.2 %

Procedure:
Thioacetamide (120 mg) was added to an ethanol (6 mL) solution of tert-butyl 4-(bromoacetyl)piperazinecarboxylate (340 mg) obtained in the above 1), and heated under reflux for 3 hours. The reaction liquid was restored to room temperature, then the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 7 mg of the entitled compound.
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9](=[O:17])[N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9]([N:10]1[CH2:15][CH2:14][C:13](=[N:32][OH:33])[CH2:12][CH2:11]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(=NO)CC1)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-1H-indole-2-carboxylic acid [1(S)-benzyl-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-amide (406 mg, 0.96 mmol) , hydroxylamine hydrochloride (80 mg, 1.15 mmol), and potassium carbonate, (159 mg, 1.15 mmol) in ethanol (6 mL) and water (1 mL) was stirred at 25° C. for 18 h and concentrated. The residue was dissolved in ethyl acetate and the resulting solution washed with water and dried (411 mg, 98%): HPLC (60/40) 5.13 minutes (97%); TSPMS 439/441 (MH+, 100%);
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N:14]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Yield: 55.3 %

Procedure:
The title intermediate is prepared from 4-(chlorosulfonyl)benzoic acid (CAS 10130-89-9) (662 mg, 3.0 mmol) and morpholine (522 mg, 6.0 mmol) in a manner substantially similar to Procedure F to provide 450 mg (55%) of the title compound. MS (ES+) 272.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[CH:12]=[C:11]([CH3:13])[S:10][C:7]=2[NH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[C:7]2[S:10][C:11]([CH3:13])=[CH:12][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2c(=O)c([N+](=O)[O-])c[nH]c2s1
Product: Cc1cc2c(Cl)c([N+](=O)[O-])cnc2s1
Yield: 68 %

Procedure:
A mixture of 2.26 g of 5-nitro-2-methylthieno[2,3-b]pyridine-4(7H)-one 2 and 10 ml of phosphorus oxychloride is refluxed for 1 hour. The reaction mixture is concentrated to dryness in vacuo and the residue is taken up on ethyl acetate. The organic phase is dried over magnesium sulfate and treated with activated charcoal. The mixture is filtered and the solvent is evaporated in vacuo. The crude product is recrystallized from ethyl acetate-n-hexane to give 1.90 g (68%) of Compound 3 as colorless crystals melting at 96°-98° C.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][NH:29][CH3:30])[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:1][N:2]([CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[CH2:28][N:29]([CH3:30])[C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=2)[CH2:19][CH2:18]1)[S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CNC/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reactant: Cc1nccc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccc(N(C)C/C=C/COC[C@H]2CC[C@H](CN(C)S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C

Procedure:
A solution of 77 mg (0.17 mmol) trans-N-methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide (example 20.6), 0.044 g (0.34 mmol) of 4-chloro-2-methyl-pyrimidine [Ger. Offen. (1990), DE3905364 A1] and 0.06 ml (0.34 mmol) N-ethyl-diisopropylamine in 1 ml of N,N-dimethylformamide was stirred for 2 hours at 80° C. The reaction mixture was then cooled to room temperature, poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 95:5:1 v/v/v mixture of dichloromethane, methanol and saturated aqueous ammonia as the eluent giving 55 mg (59%) trans-N-methyl-N-(4-{4-[methyl-(2-methyl-pyrimidin-4-yl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-4-trifluoromethyl-benzenesulfonamide as yellowish viscous oil, MS: 541 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10](O)[CH:11]([CH3:13])[CH3:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]([CH3:13])[CH3:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CS
Reactant: CC(C)C(O)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 77.5 %

Procedure:
A mixture comprising 2 g of 1-(1,3-benzodioxol-5-yl)-2-methyl-1-propanol, 1.3 g of mercaptoacetic acid, a catalytic amount of p-toluenesulfonic acid and 50 ml of benzene was heated under reflux for 5.5 hours, followed by the addition of ethyl acetate. The mixture was washed with water and extracted with a 2N aqueous solution of sodium hydroxide. The aqueous layer was washed with chloroform, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in a vacuum to obtain a residue. This residue was purified by silica gel column chromatography (chloroform/methanol=20:1) to obtain 2.14 g of the title compound as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][CH2:20][N:21]([C:30]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:31])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:33]([O:32][C:30]([N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:19][CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCOC(=O)N(CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C)CCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N(CCCSc1nc2ccccc2n1CC(=O)O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A solution of tert-butyl{2-[3-(butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazol-1-yl}-acetate (Precursor K-01b, 200 mg, 0.38 mmol) is dissolved in TFA/dichloromethane (1:1, 3 ml). The resulting solution is allowed to stir at rt overnight. The solvent is evaporated under reduced pressure and the crude product is triturated in Et2O (2 ml) until a solid forms. It is filtered, washed thoroughly with Et2O and dried under high vacuum, yielding quantitatively the title compound (179 mg) as a white powder: tR=6.82 min (LC-1), ESI-MS (neg.): m/z 470.19 [M−H]+, ESI-MS (neg.): m/z 468.32 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 0.82 (t, 3H, CH2CH3), 1.29 (m, 2H, CH2CH3), 1.48 (quint., 2H, OCH2CH2), 1.71 (m; 2H, SCH2CH2), 2.67 (bs, 2H, PhCH2), 3.12 (m, 4H), 3.26 (bs, 2H, PhCH2CH2N), 3.94 (bs, 2H, OCH2), 4.77 (s, 2H, CH2CO2), 7.05 (s, 2Harom), 7.08-7.18 (m, 6Harom), 7.53 (m, 1Harom).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(N(C(C)C)C(C)C)C.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:33]2[CH2:34][CH2:35][CH:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C#N)c(Cl)n1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c(C#N)c(N2CCC(c3ccc(F)cc3)CC2)n1
Yield: 78.3 %

Procedure:
A dispersion of 0.5 g (2.3 mmol) of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (J. Heterocycl. Chem. 1971, 8, 445-453) and 0.65 g (5.0 mmol) of N-ethyl-diisopropylamine in 40 ml of dioxane was treated at room temperature with 0.54 g (5.0 mmol) of 4-(4-fluorophenyl)-piperidine hydrochloride during 18 h. For the working-up, the reaction mixture was evaporated, and, thereafter, the residue obtained was directly chromatographed on silica gel using toluene as the eluent yielding 660 mg (1.8 mmol, 80% of theory) of 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methylsulfanyl-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=363.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)=[CH:5][CH:4]=1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:28]([N:24]1[CH:23]=[C:22]2[C:26]([CH:27]=[C:19]([C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:4][CH:5]=4)[N:17]4[C:12]=3[C:13]([NH2:18])=[N:14][CH:15]=[N:16]4)[CH:20]=[CH:21]2)=[N:25]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCCCC1
Reactant: NCc1ccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)cc1
Product: Nc1ncnn2c(-c3ccc(CNC4CCCCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 23 %

Procedure:
Using a procedure similar to that of Example 111 with 7-(4-Aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and cyclohexanone as starting materials, 27 mg (23%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (s, 2 H) 2.4 (m, 1 H), 1.80 (m, 2 H), 1.60 (m, 2 H), 1.20-1.10 (m, 6 H); ES-MS m/z 528.06 [M+H]+, HPLC RT (min) 2.72.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[O:8][C:4]=2[CH:3]=1.[C:12](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:12])[O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: Oc1ccc2nc(S)oc2c1
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CSc1nc2ccc(O)cc2o1
Yield: 25.2 %

Procedure:
A mixture of 6-hydroxy-2-mercaptobenzoxazole (165 mg), sodium bicarbonate (84 mg) and dimethyl sulfate (94 μl) was dissolved in water (2 ml) with stirring and under an argon atmosphere. The reaction mixture was stirred at RT overnight and HPLC showed that all starting material was gone. The reaction mixture was evaporated to dryness to give a dark brown solid (one can also extract the reaction mixture with chloroform to give the crude product). Chromatography on silica gel using 10% ethyl acetate/hexane gave the pure product as a near-white crystalline solid (45 mg, 25%).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8]1(=[O:13])[O:12][CH2:11][CH2:10][O:9]1>>[CH2:1]([NH:7][C:8](=[O:13])[O:9][CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1OCCO1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)OCCO
Temperature: 70 °C
Reaction time: 5 h

Procedure:
N-hexylamine (8.8 g, 100 mmole) and ethylene carbonate (10.12 g, 100 mmole) was mixed into a solution, and the solution is then further heated to 70° C. After reacting for 5 hours, the product was purified by vacuum distillation (128-130° C./0.05 mmHg) to form 2-hydroxyethyl N-hexyl-carbamate (compound I), 15.1 g (yield: 80%), which is an achromatic oily liquid. 2-hydroxyethyl N-hexyl-carbamate (compound I, 4.73 g, 25 mmole), benzaldehyde dimethylacetal (3.79 g, 25 mmole), and a catalyst of p-toulenesulfonic acid (0.05g) are mixed. Thus, the mixed solution was gradually heated to 160° C. and then reacted for 2 hours. Methanol formed in the period is then removed. Thereafter, the mixed solution was processed by vacuum distillation (0.01 mmHg) and heated to 200° C. A thermally decomposable polymer (A) (poly(N,O)acetal, PA) 5.5 g (yield: 65%) was obtained after 2 hours, which is a highly viscous oily constituent with orange-red color. Referring to the reaction formula below, the synthesis procedure of the thermally decomposable polymer (A) is shown below:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]([NH2:14])=O)=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21].O.[OH-].[NH4+]>C(#N)C>[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:11]([C:12]#[N:14])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 75.3 %

Procedure:
Phosphorus pentachloride (1.082 g) is added over about 30 minutes into a mixture of 4-methyl-3,5-dinitrobenzamide (6) (1.04 g) in acetonitrile (20 mL, 15 g). The mixture is then heated to about 60° C. for about 4 hours. The solution is then cooled to ambient temperature and is slowly added to an ice and water mixture (20 mL). The mixture is cooled to about 5° C., whereupon ammonium hydroxide is added until a pH of about 8 is attained. The product that precipitates is filtered, washed with water (10 mL), and dried to provide 4-methyl-3,5-dinitrobenzonitrile (4) (0.72 g, 75% Yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[CH3:18][O:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@@H:11]1[CH2:16][CH2:15][C@H:14]([NH:25][CH2:24][CH2:23][O:22][C:21]2[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=2[O:19][CH3:18])[CH2:13][CH2:12]1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: COc1ccccc1OCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccccc1OCCN[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (0.38 g, 1.6 mmol), [2-(2-methoxy-phenoxy)-ethyl]-amine (0.27 g, 1.6 mmol), sodium triacetoxyborohydride (0.5 g, 2.2 mmol) and acetic acid (0.06 ml, 1.8 mmol) in 1,2-dichloroethane (8 ml) was allowed to stir at room temperature for 4 hours. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.43 g (71%) of product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].I[CH3:22].[H-].[Na+].Cl>O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][CH3:22])#[N:2]
Reactant: CI
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (100 mg, 0.375 mmol) and iodomethane (0.070 mL. 1.1 mmol) in 1V,N-dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 45 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h. Water and 1 M HCl were added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with hexane/diisopropyl ether to give 5-(4-cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (92 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]#[N:22].C(COC)[O:24]C>O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Ru]>[NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)[C:3]=1[C:21]([NH2:22])=[O:24]
Reactant: COCCOC
Reactant: COC(=O)c1ccc(-c2nn(C(C)(C)C)c(N)c2C#N)cc1
Agent: [Ru]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC(=O)c1ccc(-c2nn(C(C)(C)C)c(N)c2C(N)=O)cc1

Procedure:
A mixture of 5-amino-1-tert-butyl-4-cyano-3-(4-methoxycarbonylphenyl)pyrazole (448 mg, 1.5 mmol) and tetrakis(triphenylphosphine)ruthenium dihydride in dimethoxyethane (1 ml) and water (54 μl) was heated at 120° under a nitrogen atmosphere in a sealed tube for 18 h. The reaction was concentrated under reduced pressure and the residue subjected to column chromatography (silica 4% methanol-CH2Cl2) to give the title compound (170 mg) after recrystallisation from ethyl acetate as a colourless solid m.p. 237-239°. δH (CDCl3) 1.67 (9H, s), 4.39 (3H, s), 5.10 (2H, br s), 5.69 (2H, br s), 7.66 (2H, d, J 8.2 Hz), and 8.11 (2H, d, J 8.3 Hz).