Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[N:11][CH:12]=1>COCCOC>[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:10]=[N:11][CH:12]=1
Reactant: Nc1cncc(Br)c1
Reactant: CCN=C=O
Solvent: COCCOC
Product: CCNC(=O)Nc1cncc(Br)c1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
A mixture of EtNCO (1.6 ml, 20 mmol) and 5-bromo-pyridin-3-ylamine (1.73 g, 10 mmol) in DME (10 ml) was stirred and heated at 60° C. under N2. After 2 hours another aliquot of EtNCO (1.6 ml, 20 mmol) was added and the mixture was stirred at 60° C. for a further 16 hours. After cooling to RT the mixture was evaporated. The residue was triturated with EtOAc. The solid was collected by filtration and dried under vacuum to give the title compound (2.2 g) as a colourless solid. 1H NMR (400 MHz, DMSO-d6): 8.85 (1H, s), 8.43 (1H, d), 8.27 (1H, t), 8.21 (1H, d), 6.39 (1H, t), 3.19-3.05 (2H, m), 1.06 (3H, t).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH:20]([F:22])[F:21])=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:9]=1.FC(F)(F)S(O[CH:29]([CH2:35][CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)=O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH:20]([F:22])[F:21])=[C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:29]([CH2:35][CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12](=[O:18])[CH:11]=2)[CH:9]=1
Reactant: CCOC(=O)C(CC)OS(=O)(=O)C(F)(F)F
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon and at RT, 105 mg (2.64 mmol, 1.3 eq.) of sodium hydride (60% in mineral oil) were added to a solution of 618 mg (2.03 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one in 25 ml of tetrahydrofuran, the mixture was stirred at RT for 60 min 871 mg (2.64 mmol, 1.3 eq.) of ethyl 2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) [J. Castells et al. Tetrahedron, 1994, 50, 13765-13774] were then added dropwise and the mixture was stirred at RT for 1 h. A further 38 mg (0.96 mmol) of sodium hydride (60% in mineral oil) were added, the reaction mixture was stirred at RT for 5 min, a further 871 mg (2.64 mmol, 1.3 eq.) of ethyl 2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) were added dropwise, and the reaction mixture was stirred at RT for 15 min and then quenched with water. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 415 mg (48% of theory)
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13]>C(#N)C>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[S:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: Cc1cccc2sc(NC(=S)n3ccnc3)nc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
To 4-methylbenzo[d]thiazol-2-amine (1.1 g, 6.7 mmol) in acetonitrile (30 mL) was added 1,1′-thiocarbonyldiimidazole (1.552 g, 8.71 mmol). The reaction mixture was stirred at 50° C. for 18 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with acetonitrile (2×50 mL). The yellow powder was dried in a vacuum oven (50° C.) for 1 hour to yield N-(4-methylbenzo[d]thiazol-2-yl)-1H-imidazole-1-carbothioamide (900 mg, 3.28 mmol, 49% yield) and then used in the next step without any further purification or characterization.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1>C(Cl)(Cl)Cl.CN(C=O)C>[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([S:17]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2o1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nc2ccc(S(=O)(=O)N3CCCCC3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Piperidine (2.2 g, 26 mmol) was added drop wise to a solution of Compound 8 (3.0 g, 10 mmol) in chloroform (30 ml) and DMF (10 ml). The combined mixture was stirred at room temperature for 1 hour, and then washed with water (2×, 50 ml) and brine (1×, 50 ml). The organic layer was then dried over sodium sulfate and evaporated to provide 2.76 g (76%) of Compound 9 as a sticky white solid. TLC analysis showed Rf=0.25 (30% ethyl acetate in hexane). The structure of this compound is given below:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:14])=[N:4][C:5]([F:13])=[C:6]([Cl:12])[C:7]=1[CH2:8]C(O)=O.[Br:15]Br>ClC1C=CC=CC=1.[Hg]=O>[Br:15][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([F:14])[N:4]=[C:5]([F:13])[C:6]=1[Cl:12]
Reactant: BrBr
Reactant: O=C(O)Cc1c(Cl)c(F)nc(F)c1Cl
Agent: O=[Hg]
Solvent: Clc1ccccc1
Product: Fc1nc(F)c(Cl)c(CBr)c1Cl
Temperature: 145 °C
Yield: 83.2 %

Procedure:
To a 1 L 3-neck flask equipped with addition funnel, was placed chlorobenzene (150 ml). 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetic acid (21 g, 86.77 mmol) and mercury oxide (20 g, 92.34 mmol) were added in this order. The mixture was heated up to 140-150° C. in an oil bath. Bromine (5.4 mL, 105 mmol) in chlorobenzene (90 ml) was then added dropwise through the addition funnel for 2˜2.5 hr. After the addition of bromine solution, the reaction mixture was refluxed for further 1 hr. and cooled to room temperature. The mixture was filtered through celite pad and the pad was washed with chlorobenzene. The combined filterate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:10)) to give 20 g (80%) of 4-(bromomethyl)-3,5-dichloro-2,6-difluoropyridine as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.66 (2H, s). m/z (EI) 277 (M+).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21]>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:25][CH2:24][CH2:23][N:22]([CH2:26][CH3:27])[CH2:20][CH3:21])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: CCN(CC)CCN
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(CC)CCN=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirring, refluxing suspension of 84.4 g (0.4) of 6-nitroveratraldehyde and 1.0 ml glacial acetic acid in 750 ml ethanol was aded gradually a solution of 2-diethylaminoethylamine in 50 ml ethanol. The solution was refluxed and stirred for 1 hr; the solvents were then removed in vacuo. The residue was taken up in 300 ml chloroform; the solution was washed with three 150-ml portions of water, dried over magnesium sulfate, and concentrated to dryness in vacuo to give 123 g (100%) of the product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1([C:8]([O:10]CC)=O)[CH2:7][CH2:6]1)=[O:4].[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>C1COCC1>[CH3:13][C@@H:14]([N:21]1[CH2:2][C:3](=[O:4])[C:5]2([CH2:6][CH2:7]2)[C:8]1=[O:10])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)C1(C(=O)CBr)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1CC(=O)C2(CC2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
To a solution of ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate (4.7 g, 20 mmol) in THF (60 mL) was added (R)-α-methylbenzylamine (2.9 g, 24 mmol) and Et3N (4.04 g, 40 mmol). After stirring at rt for 3 days, the reaction mixture was concentrated in vacuo, and the residue was extracted with ethyl acetate (50 mL×2) and washed with water (30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to afford the title compound as a light yellow solid (3.66 g, 80%).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9](=O)[NH:10][C:11]([C:17]2([CH3:25])[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19][CH2:18]2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]1[CH2:37][CH2:36][N:35]2[C:30](=[N:31]CCC2)[CH2:29][CH2:28]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.NCC1C=CC=CN=1>CC#N>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:35][CH2:36][C:37]2[CH:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[N:10][C:11]([C:17]2([CH3:25])[CH2:18][O:19][C:20]([CH3:24])([CH3:23])[O:21][CH2:22]2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC1(C)OCC(C)(c2nc3cccc(-c4ccccc4)c3c(=O)[nH]2)CO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CC#N
Product: CC1(C)OCC(C)(c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)CO1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 5-phenyl-2-(2,2,5-trimethyl-1,3-dioxan-5-yl)quinazolin-4(3H)-one (0.22 g, 0.62 mmol) in MeCN (10 mL) at room temperature was added DBU (0.24 g, 1.57 mmol) and BOP reagent (0.36 g, 0.81 mmol). Upon completion of addition, the reaction mixture was stirred for 30 min. Aminomethylpyridine (0.11 ml, 1.13 mmol) was added and the resulting mixture was stirred for an additional 16 h. After this time, the reaction mixture was concentrated and purified by silica gel column chromatography (2% MeOH in DCM) to provide 5-phenyl-N-(pyridin-2-ylmethyl)-2-(2,2,5-trimethyl-1,3-dioxan-5-yl)quinazolin-4-amine (0.18 g, 68% yield) as a white solid. LCMS Method V: retention time 2.21 min, [M+1]=531.2.
Reaction SMILES: CC[C@@H]([C@H](NC([C@@H](NC(CNC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@H]1NC(=O)[C@H]([C@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@@H](NC([C@@H](N)CCCCN)=O)CSSC1)=O)C)=O)[C@H](O)C)=O)CCC(N)=O)=O)CCCNC(N)=N)=O)CC(C)C)=O)C)=O)CC(N)=O)=O)CC1C=CC=CC=1)=O)CC(C)C)=O)C(C)C)=O)CC1NC=NC=1)=O)CO)=O)CO)=O)CC(N)=O)=O)CC(N)=O)=O)CC1C=CC=CC=1)=O)=O)C)=O)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H:76]([C:85]([OH:87])=[O:86])[CH2:77]C1C=CC(O)=CC=1)=O)[C@H](O)C)=O)CC(N)=O)=O)CO)=O)=O)C(C)C)=O)CC(N)=O)=O)[C@H](O)C)=O)CO)=O)CO)=O)CC(C)C)=O)C.[O:274]=[CH:275][C@@H:276]([C@H:278]([C@@H:280]([C@@H:282]([CH2:284][OH:285])[OH:283])[OH:281])[OH:279])[OH:277]>>[O:274]=[CH:275][C@@H:276]([C@H:278]([C@@H:280]([C@@H:282]([CH2:284][OH:285])[OH:283])[OH:281])[OH:279])[OH:277].[C:85]([O-:87])(=[O:86])[CH:76]([CH3:77])[OH:274]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)[C@@H](C)O)C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)[C@@H](C)O)C(C)C)[C@@H](C)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(O)C(=O)[O-]

Procedure:
At t=30, vehicle, or amylin ±AC-0253 was begun. Amylin dose rates were 50, 100 and 300 pmol/kg/min. Dose rates of AC-0253 were 500 and 1500 pmol/kg/min. 25% glucose (1 gm/kg) was administered by mouth at t=0 minutes. Amylin ±AC-0253 was discontinued at t=120 minutes. Samples for insulin, glucose and lactate were obtained at 15 minutes intervals from t=−45 to t=180 minutes. Samples for rat amylin and AC-0253 were taken at t=60 and 120 minutes.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH2:21][C:22]([OH:24])=O)[CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+:25].[OH-]>>[C:22]([CH2:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1)(=[O:24])[NH2:25]
Reactant: O=C(O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1

Procedure:
The carboxylic acid (10) (50 mg, 0.15 mmol) was coupled to NH4OH (0.01 ml, 0.15 mmol) using Method C. The crude compound was purified by column chromatography, eluting with a stepped gradient of 80-100% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1.[CH2:12]([Mg]Br)[CH3:13].O.Cl>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH3:11])[N:10]=2)[N:7]=1)[CH3:13]
Reactant: CC[Mg]Br
Reactant: Cc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCc1ccc2nc(C)cn2n1
Temperature: 25 °C

Procedure:
6-Chloro-2-methylimidazo[1,2-b]pyridazine (5.00 g, 29.8 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) dichloride (0.08 g, 0.15 mmol) were suspended in dry ether (40 ml)-dry THF (20 ml), and a solution of ethylmagnesium bromide in ether (3 M, 15 ml, 45 mmol) was added dropwise thereto with stirring under ice-cooling over 5 minutes (internal temperature 10° C. or less). The temperature of the reaction solution was increased to room temperature, and the mixture was stirred at the same temperature for 2 hours and under reflux with heating for 3 hours. The reaction solution was left to cool to room temperature under stirring, and water (30 ml) was added little by little. Further, the pH of reaction mixture was adjusted to about 5 to 6 with concentrated hydrochloric acid under stirring at room temperature. The organic layer and the aqueous layer were separated from each other, and the aqueous layer was extracted with ethyl acetate (70 ml×2). The organic layers were combined and washed with water (250 ml×3). The organic layer was dried over magnesium sulfate and concentrated, and the residues were purified by silica gel column chromatography (chloroform:ethyl acetate=2:1→1:1), and the resulting crude oil was further purified by silica gel column chromatography (ethyl acetate), and the title compound was obtained as pale red oil. The yield was 1.32 g (27.4%).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=1>N1C=CC=CC=1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([O:20][CH2:19][N:15]2[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]3[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:29]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)=[O:30])[C:4](=[O:22])[CH2:5]3)[CH2:17][C:16]2=[O:18])=[O:30])[CH:24]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Solvent: c1ccncc1
Product: O=C(OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)c3cccnc3)C(=O)C2)CC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
A mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (0.31 g, 1.0 m mol), 3-pyridylcarbonyl chloride (0.28 g, 2.0 m mol) and pyridine (10 ml) was stirred for 18 hours at room temperature. The solvent was removed from the reaction mixture under reduced pressure and the residue was extracted with chloroform. The extract solution was washed with saturated sodium bicarbonate aqueous solution successively with water, and was dried over magnesium sulfate. The residue obtained by removing the solvent under reduced pressure from the extract solution was purified by silica gel column chromatography (chloroform:ether:methanol=6:1:1, Rf value=0.3) to give the titled compound (0.12 g; yield 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:22][CH2:23][CH2:24][CH3:25].Br[CH2:27][C:28]1C2C(=CC=C(C3C=CC=CC=3OC)C=2)NC(C)(C)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(N)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:25][CH:24]=1
Reactant: CCCNCC1=CC(C)(C)Nc2ccc(-c3ccccc3OC)cc21
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCN
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]propylamine 44 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 30 μL of 1-propylamine reacted to give 4.6 mg of the title compound as a foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][OH:14].Cl.C([O-])(O)=O.[Na+].CO>O>[OH:14][NH:13][C:11](=[NH:12])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: NO
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(Cc1ccc([N+](=O)[O-])cc1)NO
Temperature: 25 °C

Procedure:
A 250-mL round bottomed flask was charged with 2-(4-nitrophenyl)acetonitrile (2.5 g, 15.4 mmol, 1 eq.), NH2OH/HCl (2.12 g, 31 mmol, 2 eq), NaHCO3 (2.82 g, 2.3 mol, 7 eq.), MeOH (100 ml) and water (16 ml). The mixture was stirred under reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure. The residue was treated with water (100 ml). Solid was collected by filtration and washed with water (3×20 ml) followed by dichloromethane (3×10 ml). After drying, the title compound was obtained as yellowish solid (2.46 g, 84% yield).
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>CC1C=CC(C(C)C)=CC=1>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([OH:18])=[O:17]
Reactant: O=C1CCCCO1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C(O)CCCCc1c[nH]c2ccc(F)cc12
Reaction time: 80 h
Yield: 21.8 %

Procedure:
In a water separator, 5-fluoroindole (5.0 g, 37 mmol.), δ-valerolactone (3.83 ml, 42 mmol.), potassium hydroxide (3.09 g, 55 mmol.) in p-cymene (120 ml) were heated to boiling, with stirring. The water separation was stopped after 80 h. For working up, water (50 ml) was added to the mixture at RT and stirring was carried out for 30 min. The phases were then separated in a separating funnel. The aqueous phase was washed with ether (3×20 ml), adjusted to pH 1 with 2M HCl and extracted with ether (5×25 ml). The combined extracts were washed with water (5×10 ml), dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (375 g) (eluant: 2700 ml of cyclohexane/EE 4:1 followed by 1500 ml of cyclohexane/EE 1:1 and 650 ml of EE). 1.9 g of 5-(5-fluoro-1H-indol-3-yl)pentanoic acid were obtained (beige solid, m.p. 86–92° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].Cl[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][C:5]1([CH3:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:18]=[N:17][N:16]=3)[CH:3]=2)[C:7](=[O:11])[NH:6]1
Reactant: CC1(C)NC(=O)c2ccc(O)cc21
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)NC(=O)c2ccc(Oc3nnnn3-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of lactam 62 (1.77 g, 10.0 mmol) and 5-chloro-1phenyl-1H-tetrazole (2.17 g, 12.0 mmol) in dry DMF (50 mL) is treated with solid K2CO3 (2.07 g, 15.0 mmol). The mixture is stirred overnight at rt, then poured into water and extracted with EtOAc (2×). The organic phase is washed with water (3×) and brine (2×), then dried (MgSO4), filtered, and evaporated. The residue is crystallized from CH2Cl2 to give a white solid, mp 202-204° C. The material weighs 3.10 g (97% yield) . 1H NMR (CDCl3) 7.90 (d, 1, J=8.3), 7.80 (m, 2), 7.60-7.55 (m, 4), 7.50-7.45 (m, 1), 6.78 (s, 1), 1.59 (s, 6); 13C NMR (CDCl3) 168.45, 158.80, 156.15, 155.27, 132.83, 129.81, 128.77, 125.78, 122.33, 119.44, 112.11, 59.14, 53.39, 27.59; MS (MW=321.3, EI, eE=70 eV) m/z 321 (M+), 306, 293, 278, 261, 250, 236, 222, 208, 187, 176, 161 (base peak), 145, 133, 117, 103, 91, 77, 65, 42.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]2([C:37]([F:40])([F:39])[F:38])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([N:26]4C(=O)C5=CC=CC=C5C4=O)[CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.NN>C(O)C>[NH2:26][CH:24]([C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH2:14][C:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:42])([F:41])[F:1])[CH:4]=3)([C:37]([F:38])([F:39])[F:40])[O:17][N:16]=2)=[CH:23][CH:22]=1)[CH3:25]
Reactant: CC(c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(N)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2.80 g of N-[1-[4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl]ethyl]phthalimide in 10 mL of ethanol, 0.22 g of hydrazine monohydrate was added and the resultant reaction mixture was stirred at 80° C. for 2 hours. After the completion of the reaction, the mixture was cooled down to 0° C. and the deposited insoluble substance was filtered off, followed by cleaning the filtered substance with a small amount of chloroform. The filtrate and the resultant chloroform-cleaning liquid were combined and the solvent was distilled off under reduced pressure. The resultant residue was dissolved in 30 mL of ethyl acetate and the resultant solution was washed with water (10 mL×1). Subsequently, the washed solution was dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order, and the solvent was distilled off under reduced pressure to obtain 1.80 g of the objective substance as a yellow resinoid. This was used in the next process as it was without being further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6]O.P(Br)(Br)[Br:14]>COCCOC>[Br:14][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[Cl:1]
Reactant: OCCOc1ccc(Cl)cc1Cl
Reactant: BrP(Br)Br
Solvent: COCCOC
Product: Clc1ccc(OCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.2 %

Procedure:
To a solution of 10.0 g of 2-(2,4-dichlorophenoxy)-1-ethanol in 1,2-dimethoxyethane (200 ml) was added dropwise a solution of 14 g of phosphorus tribromide in 1,2-dimethoxyethane (20 ml) under ice-cooling. The reaction solution was stirred at room temperature for 20 hours. After the reaction solution was concentrated, the residue was diluted with water and ethyl acetate. Saturated aqueous sodium hydrogencarbonate was added to the organic layer, and the resulting emulsion formed was subjected to Celite filtration. The filtrate was diluted with diethyl ether and saturated aqueous ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography, to give 6.15 g of the title compound as a pale yellow oil.