Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]4[CH:22]([CH2:28][CH3:29])[CH2:23][C:24](=[O:27])[NH:25][N:26]=4)[CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:8][CH:7]=1.Cl.O1CCOCC1>CC(=O)OCC>[CH2:28]([CH:22]1[CH2:23][C:24](=[O:27])[NH:25][N:26]=[C:21]1[C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]=[O:2])=[CH:7][CH:8]=3)[O:13][C:14]=2[CH:20]=1)[CH3:29]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(OC)OC)cc3)oc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC=O)cc3)oc2c1

Procedure:
22.2 mg (52 μmol) 6-{2-[4-(2,2-dimethoxy-ethoxy)-phenyl]-benzoxazol-6-yl}-5-ethyl-4,5-dihydro-2H-pyridazin-3-one, 130 μL (4 mmol/mL; 520 μmol) HCl and 2 ml dioxane are stirred for 3 h at 50° C. Then the mixture is diluted with EA, extracted with H2O and then with 10% sodium carbonate solution. The solv. of the org. phase is eliminated i.V.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[N:6][CH:7]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:13][CH:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9]([F:10])([F:11])[F:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1cncc(Br)c1)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)OC(c1cncc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
In pyridine (2.0 mL) was dissolved 1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethanol (390 mg, 1.52 mmol) obtained in Step 2. Acetic anhydride (2.0 mL) was added and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and a saturated aqueous sodium bicarbonate solution and water were added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and further purified by preparative thin-layer chromatography (hexane/ethyl acetate=4/1) to give 1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethyl acetate (429 mg, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2].[C-:25]#[N:26].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10]([C:25]#[N:26])[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](C#N)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 96 h

Procedure:
A mixture of (4R)-1-(tert-butyloxycarbonyl)-4-(methane-sulfonyloxy)-L-proline tert-butyl ester (889 mg, 2.43 mmol) and sodium cyanide (1.19 g, 24.3 mmol) in N,N-dimethylformamide (18 mL) was stirred for 4 days at 80° C. under a nitrogen atmosphere. The cooled reaction mixture was diluted with ethyl acetate (100 mL), washed with water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting initially with 10% ethyl acetate/hexane. Fractions containing the TLC more mobile isomer were combined and evaporated to afford the desired title compound; yield 225 mg (31%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])N)=[CH:4][CH:3]=1.CO[CH:22](OC)[CH2:23][CH2:24][CH2:25][NH:26][CH3:27]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])[CH:22]=[C:23]2[CH2:24][CH2:25][NH:26][CH3:27]
Reactant: CNCCCC(OC)OC
Reactant: CC1CCN(C(=O)CN(N)c2ccc(Cl)cc2)CC1
Product: CNCCc1cn(CC(=O)N2CCC(C)CC2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 2-(1-(4-chlorophenyl)hydrazinyl)-1-(4-methylpiperidin-1-yl)ethanone (Example 6) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[CH:16]=O)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)[C:3]=1[C:31]([NH2:33])=[O:32]>CO.C(Cl)Cl.CC(O)=O>[N+:13]([C:11]1[CH:12]=[C:7]2[C:8]([CH:16]=[N:1][C:2]3[N:6]2[N:5]=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][CH:23]=2)[C:3]=3[C:31]([NH2:33])=[O:32])=[CH:9][CH:10]=1)([O-:15])=[O:14]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2C=O)c1N
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1ncc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
To a solution of 5-amino-1-(2-formyl-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (400 mg, 0.9 mmol) in 5 mL of CH3OH and 5 mL of DCM was added HOAc (1 drops). After stirring at RT for 16 hr, the mixture was concentrated and purified by chromatography column on silica gel eluting with PE/EA to afford 240 mg (63%) of 8-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 425.8.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:8]=[CH:9][N:10]=1.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[F:40][S:37]([F:38])([F:39])([F:41])([F:42])[C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH2:5][CH2:4][OH:3])=[CH:20][CH:19]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 130 mg (0.50 mmol) 4-{4-[2-(2-Hydroxyethyl)-imidazol-1-yl]-butyl}-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was filtered, dried and purified by chromatography on silica (ethyl acetate/methanol 8:1) to give 133 mg (47%) amorphous material.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([F:20])=[CH:17][C:18]=1[I:19])([CH3:6])([CH3:5])[CH3:4].[CH3:22]I>CN(C=O)C>[C:3]([O:7][C:8](=[O:21])[N:9]([CH2:10][CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([F:20])=[CH:17][C:18]=1[I:19])[CH3:22])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCOc1cnc(F)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1cnc(F)cc1I)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
Add sodium hydride (620 mg, 26 mmol) to a solution of [2-(6-fluoro-4-iodo-pyridin-3-yloxy)-ethyl]-carbamic acid tert-butyl ester (0.33 g, 0.86 mmol) in 3 mL of DMF. Stir the mixture at RT for 1 h and add methyl iodide (0.37 g, 2.59 mmol). Stir the reaction mixture at RT overnight. Add water and extract with ethyl acetate. Wash the organic layer with saturated aqueous sodium chloride. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify the residue by column chromatography (20% ethyl acetate in hexane) to afford the title compound as a light yellow solid (0.13 g, 38%). 1H NMR (400 MHz, CD3CN) δ 1.45 (s, 9H), 3.08 (s, 3H), 3.59 (t, J=5.6 Hz, 2H), 4.20 (t, J=5.6 Hz, 2H), 5.07 (s, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([OH:15])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]=[C:19]=[O:20]>CS(O)(=O)=O.ClCCl>[CH3:17][NH:18][C:19]([O:15][CH:10]1[C:9]2[CH:8]=[C:7]([CH3:16])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]=2[O:12][C:11]1=[O:14])=[O:20]
Reactant: CN=C=O
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CNC(=O)OC1C(=O)Oc2c1cc(C)cc2C(C)(C)C
Yield: 65 %

Procedure:
A mixture of 5.5 g (25.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (102), Example 2), 3 ml (50.0 retool) of methyl isocyanate and 2 drops of methanesulfonic acid is refluxed for 3 i/4 hours. Then 3 ml (50.0 retool) of methyl isocyanate and 2 drops of methanesulfonic acid are again added. The reaction mixture is refluxed for a further 16 hours, then cooled, diluted with dichloromethane and washed with water and 5% aqueous sodium hydrogencarbonate solution. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from toluene yields 4.45 g (65%) of 3-(N-methylcarbamoyloxy)-5-methyl-7-tert-butyl-3H-benzofuran-2-one (corn pound (112), Table 1 ), m.p. 138°-143° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[N:17]1([CH2:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>Cl>[ClH:8].[N:17]1([CH2:22][CH:23]2[CH2:28][CH2:27][C:26]3([NH:1][C:2]4[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][C:3]=4[S:13](=[O:15])(=[O:14])[NH:16]3)[CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCC(CN2CCCC2)CC1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1S(N)(=O)=O
Agent: Cl
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC1(CCC(CN3CCCC3)CC1)NS2(=O)=O
Yield: 168.9 %

Procedure:
A mixture of 4-amino-6-chloro-1,3-benzenedisulfonamide (5.72 g., 0.02 mole) and 4-(1-pyrrolidinylmethyl) cyclohexanone (5.0 g., 0.027 mole) in 2 N ethanolic HCl (100 ml.) is refluxed one and one half hours and cooled to give 8.2 g of 4'-(1-pyrrolidinylmethyl)-6-chlorospiro[2H-1,2,4-benzothiadiazine-3(4H),1'-cyclohexane]-7-sulfonamide-1,1-dioxide hydrochloride which melts at 268°-70° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:27]O)[S:25][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)[S:25][CH:26]=1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1cc(Cl)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4cc(Cl)cs4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-chloro-thiophen-2-yl)methanol (167 mg) and tributylphosphine (338 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (422 mg), and the mixture was stirred under at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine successively, dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (MeOH/DCM) to afford the title compound as a white solid.
Reaction SMILES: C1C(=O)N(OC(CCCCCN[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]2[S:27][CH2:26][C@@H:25]3[NH:28][C:29]([NH:31][C@H:24]23)=[O:30])=[O:18])=O)C(=O)C1.C(=O)([O-])[O-:33]>>[OH:33][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:24]2[C@@H:25]([NH:28][C:29]([NH:31]2)=[O:30])[CH2:26][S:27]1)=[O:18]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Following the above-mentioned method, labeled antibodies were produced using monoclonal antibodies. Anti-α-subunit monoclonal antibody (IM0365) (5 μg/mL) dissolved in 0.1 M carbonate buffer (pH 8.5) and NHS-LC-BIOTIN (PIERCE, 25 μg/mL) were mixed and stirred at room temperature for four hours using a stirrer. IgG and NHS-LC-BIOTIN were mixed at a mole ratio of 1:60. After stiring, this solution was dialyzed against physiological phosphate buffered saline (PBS) to obtain biotin-labeled antibodies.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.N1C=CC=CC=1.Cl[C:19](OCC)=[O:20]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:7])[NH:8][C:19](=[O:20])[O:11][C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1ccc(Cl)cc1O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1[nH]c(=O)c2ccc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 22 L, five neck, round bottom flask was equipped with an overhead stirrer, reflux condenser, addition funnel, thermocouple temperature read out, and a heating mantle. The reactor was purged with nitrogen. Acetonitrile (4700 mL) and 4-chloro-2-hydroxybenzamide (1782 g, 10.4 mol) were charged to the reaction flask and the stirring was started. Pyridine (1133 mL, 14.0 mol) was charged to the reactor. The resulting reaction slurry was cooled to less than 10° C. with an ice bath. Ethyl chloroformate (1091 mL, 1237 g, 11.4 mol) was placed in the addition funnel and charged slowly to the stirred reaction mixture such that the temperature of the reaction mixture did not exceed 15° C. during the addition. The temperature of the reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours. Liquid chromatographic analysis of the reaction mixture indicated that the reaction was only 80% complete. Approximately half of the solvent was removed by atmospheric distillation. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Additional pyridine (215 mL, 2.65 mol) was added to the reaction mixture. Ethyl chloroformate (235 g, 2.17 mol) was added slowly via an addition funnel to the cold reaction mixture. The reaction mixture was held between 10 and 15° C. for 30 minutes after the ethyl chloroformate addition was complete. The ice bath was removed, and the reaction mixture was warmed to ambient temperature. The reaction mixture was then slowly heated to reflux and held at that temperature for 18 hours, after which time liquid chromatographic analysis indicated that the reaction was complete. The reaction mixture was cooled first to ambient temperature and then to <10° C. with an ice bath. Water (1600 mL) was added slowly via an addition funnel and the resulting slurry held at <10° C. for 90 minutes. The solid product was collected by vacuum filtration through a large sintered glass funnel. The product filter cake was washed with deionized water and vacuum dried at 50° C. for 18 hours to give 1914 g of 7-chloro-2H-1,3-benzoxazine-2,4(3H)-dione as a tan solid. The yield was 83%.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH:18]=[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:28])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)[CH3:6])C.[OH-].[Na+:31]>O1CCOCC1>[Na+:31].[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[CH:18][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH:5]([CH3:6])[C:4]([O-:29])=[O:3])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[C:20]1=[O:28]
Reactant: CCOC(=O)C(C)Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Oc1ccc(C=C2C(=O)Nc3ccccc32)c2cccnc12)C(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a suspension of 2-[5-(2-oxindol-3-ylidenemethyl)quinol-8-yloxy]propionic acid ethyl ester (150 mg, 0.39 mmol) in dioxane (15 ml) was added dropwise 2N sodium hydroxide (1.0 ml, 2 mmol) and the reaction mixture was stirred for another 1 h at room temperature. The crystalline precipitate was filtered and dried to give pure title compound in 73.8% yield (110 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[N:16]([O-])=O.[Na+].O.O.Cl[Sn]Cl>C(O)(=O)C.O.Cl>[NH:13]([C:12]1[CH:14]=[CH:15][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:10][CH:11]=1)[NH2:16]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(NN)cc2)CC1
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
To a stirred solution of 4-[(4-methylpiperazin-1-yl)methyl]aniline (3.2 g, 15.57 mmol) in acetic acid: concentrated HCl (32:32 mL) at 10° C. was added NaNO2 (1.30 g, 18.78 mmol) in water (16 mL) and stirred for 10 min. Freshly prepared SnCl2.2H2O (11.75 g, 51.97 mmol) in concentrated HCl (32 mL) was added at 10° C. The temperature of the reaction mixture was allowed to rise to room temperature and maintained there for 4 hr. After filtering the reaction mixture, the precipitate was washed with water and the solid obtained was dried under reduced pressure to obtain 1-(4-hydrazinobenzyl)-4-methylpiperazine (3.4 g). 1H NMR (CD3OD, 200 MHz) δ: 7.66 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 4.46 (2H, s), 3.72 (8H, bm), 3.11 (3H, s);
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:3].[CH3:46][O:47][CH2:48][CH2:49][NH:50][CH3:51]>C1(C)C=CC=CC=1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH:9]2[O:8][CH2:7][C:6]2[CH:42]=[CH:43][C:44]([CH3:45])=[C:4]([C:2](=[O:3])[N:50]([CH2:49][CH2:48][O:47][CH3:46])[CH3:51])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)Cl)c2)cc1
Reactant: CNCCOC
Solvent: Cc1ccccc1
Product: COCCN(C)C(=O)c1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 0.222 g of tert-butyl 3-(3-chlorocarbonyl-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 6 ml of toluene is admixed at 0° C. with the solution of 0.129 g of 2-methoxy-N-methylethylamine in 6 ml of toluene. The reaction mixture is stirred at 0° C. over a further 1 hour and then concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.12 (1:2 EtOAc-heptane); Rt=5.72.
Reaction SMILES: CO[N:3]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]3[C:4]1=[O:21].C(O)C.C(O)(=O)C>>[C:15]1([CH:6]2[CH2:7][CH2:8][C:9]3[C:14]4=[C:13]([NH:3][C:4](=[O:21])[N:5]24)[CH:12]=[CH:11][CH:10]=3)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COn1c(=O)n2c3c(cccc31)CCC2c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CC3
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of 1-methoxy-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (0.575 g, 2.05 mmol) in ethanol (35.9 mL, 615 mmol) was heated to dissolve residual solids and the resulting solution was cooled to room temperature. The solution was treated with acetic acid (0.233 mL, 4.10 mmol), degassed with nitrogen, treated with palladium catalyst (0.575 g, 100 wt %) (10% Pd on carbon, Degussa type) and hydrogenated for 17 h. The reaction mixture was filtered and the catalyst was washed with ethanol and methanol. The filtrate was then concentrated to give the desired product (0.436 g, 85%) as a racemic mixture that was used without further purification. LCMS calculated for C16H15N2O (M+H)+: m/z=251.1. found: 251.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)=[O:4].Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1)=[O:12])=[O:4]
Reactant: COC(=O)C1CCNCC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)N2CCC(C(=O)OC)CC2)c1

Procedure:
Methyl 1-[5-(methoxycarbonyl)-2-nitrobenzoyl]-4-piperidinecarboxylate is prepared in analogy to the process described in Example IX from 5-(methoxycarbonyl)-2-nitrobenzoic acid and methyl piperidine-4-carboxylate hydrochloride.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[OH:23][C:24]1([C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:29]1
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:6]1[O:10][C:9]([CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[O:15]1CCOCC1>>[C:1]([C:6]1[O:10][C:9]([CH:11]=[C:12]([CH3:13])[CH:14]=[O:15])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1ccc(C=C(C)C)o1
Product: CCOC(=O)c1ccc(C=C(C)C=O)o1
Temperature: 90 °C
Yield: 44 %

Procedure:
A mixture of 8.2 g (0.042 mol) of 1-(5-carbethoxy-2-furanyl)-2-methyl-1-propene, 10.0 g of SeO2 (0.09 mol) and 120 mL of dioxane was degassed three times under argon and heated at 90° C. for 1.5 h. The reaction mixture was cooled, filtered through Celite and evaporated to remove most of the dioxane. The residue was filtered again and washed with 50 mL of dioxane. The filtrate and washings were concentrated to a small volume and chromatographed on 170 g of silica gel (25% Et2O/hexane) to give 3.9 g (44% yield) of a white solid. Recrystallization from EtOAc/hexane gave long white needles, mp 83° C.; IR (mull) 1740, 1690, 1650, 1320, 1280, 1240, 1200, 1040, 980, 780 cm-1 ; 1H NMR (CDCl3) δ1.43 (t, J=7 Hz, 3, CH2CH3), 2.18 (s, 3, C=CCH3), 4.48 (q, J=7 Hz, 2, CH2CH3), 6.88 and 7.35 (2d, J=4 Hz, 2, 3', 4'H), 7.15 (s, 1, C=CH), 9.60 (s, 1, CHO); MS calcd for C11H12O4 208.0736, found 208.0728.