Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)=[O:31]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)c3ccc(Cl)cc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)c2ccc(Cl)cc2Cl)CC1
Reaction time: 15 h
Yield: 48.2 %

Procedure:
To a colorless solution of {4-[1-(2,4-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (102 mg, 0.21 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (100 mg, 4.2 mmol) in water (2.0 mL) at room temperature. The resulting colorless solution was stirred for 15 hours. The solvent was removed and the aqueous solution after dilution with water was neutralized with 1.0 N aqueous HCl. The resulting white precipitate was collected by filtration and washed with hexanes. After drying in the air, 62 mg of the crude product was isolated as a white solid. The crude product was dissolved in ethyl acetate (˜3 mL) with heating and the resulting solution was diluted with hexanes (˜20 mL). The solution was stored in the freezer for three days and the precipitated solids were collected by filtration and washed with hexanes. After drying in air, {4-[1-(2,4-dichloro-benzoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (48 mg, 48%) was isolated as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br. s, 1H), 7.85-7.97 (m, 1H), 7.81 (br. s, 1H), 7.75 (s, 1H), 7.69 (s, 1H), 7.51-7.63 (m, 1H), 7.41-7.50 (m, 1H), 7.35 (t, J=8.03 Hz, 1H), 4.71 (br. s, 1H), 3.78 (br. s, 4H), 3.40 (br. s, 2H), 2.42 (br. s, 3H), 1.77 (br. s, 2H), 1.60 (d, J=9.79 Hz, 2H). MS cald. for C25H23Cl2FNO3 [(M+H)+] 474, obsd. 474.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:12][C@H:10]([C:8]2[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]3[CH:19]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:24]=[CH:23][N:22]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccnn1C
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccnn1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(2-methyl-2H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]ethylamine, (0.093 g, 0.359 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (0.078 g, 0.502 mmol) and DIPEA (0.12 mL, 0.646 mmol) in IPA (2 mL) was stirred at 80° C. in a sealed microwave tube for 16 h. After cooling, mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. Residue was purified by silica gel chromatography eluting with 100% DCM—8% (2M ammonia in methanol) in DCM to give 416 as a white solid (0.107 g, 79%). LCMS (Method K): RT 3.16, 3.28 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 7.92-7.87 (1H, s), 7.87-7.84 (1H, m), 7.75-7.75 (1H, m), 7.60-7.54 (1H, m), 7.30-7.19 (3H, m), 6.96 (1H, m), 6.61-6.44 (1H, m), 5.47-5.38 (1H, m), 3.59-3.53 (3H, m), 3.17 (0H, d, J=5.25 Hz), 1.58-1.51 (3H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [CH2:1]([N:5]([C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C:6]1[N:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]=1[C:15](O)=[O:16])[CH2:2][CH2:3][CH3:4].CCN=C=N[CH2:32][CH2:33][CH2:34][N:35](C)C.C1C=NC2N(O)N=NC=2C=1.[CH3:48][CH2:49][O:50][C:51]1C(N)=C[CH:54]=[CH:55][CH:56]=1>C(Cl)Cl>[CH2:49]([O:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:32][C:33]=1[CH2:34][NH:35][C:15]([C:14]1[N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]2=[N:7][C:6]=1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)=[O:16])[CH3:48]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1ccccc1N
Reactant: CCCCN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)O)CCCC2
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCCCN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)NCc1ccccc1OCC)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
2-[butyl-(3-chloro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid (130 mg, 0.45 mmol), EDCI (72.9 mg, 0.38 mmol, 1.0 eq.) and HOAt (4.7 mg, 0.035 mmol, 0.1 eq.) were dissolved in DCM (3.5 mL). ortho-phenetidine (51.5 μL, 0.35 mmol) was added thereto and the solution was stirred for 16 hours at room temperature. The solvent was removed under vacuum, EtOAc (30 mL) was added thereto and the organic phase was washed a plurality of times with a 0.5 M solution of KHSO4 in water (30 mL) and saturated aqueous NaHCO3 solution (35 mL). The aqueous phases were shaken out a plurality of times with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl solution (40 mL) and dried over sodium sulphate, and the solvent was removed under vacuum. The untreated product was purified by column chromatography (SiO2, DCM→DCM/MeOH 98/2). 130 mg (73%) of the desired product 2-[butyl-(3-chloro-benzoyl)-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid were obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)O1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[CH3:34][C:30]1[N:29]([CH2:28][C:24]2[N:25]=[N:26][CH:27]=[C:22]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([CH3:19])=[CH:11][CH:10]=3)[CH:23]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c2ccccc12
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1ccc(-c2cnnc(Cn3ccnc3C)c2)c2ccccc12
Product: Cl

Procedure:
The title compound, MS: m/e=351.9 (M+H+), was prepared from 4,4,5,5-tetramethyl-2-(4-methyl-naphthalen-1-yl)-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-ylmethyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Product: CCC(NC(=O)Cc1ccc(Cl)cc1Cl)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[N:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:61][N:62]1[CH:66]=[C:65]([CH2:67][C:68](O)=[O:69])[CH:64]=[N:63]1>CN(C)C(=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][C:68](=[O:69])[CH2:67][C:65]6[CH:64]=[N:63][N:62]([CH3:61])[CH:66]=6)=[C:7]5[CH:8]=[N:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CN1C=CC(N)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Reactant: Cn1cc(CC(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NC(=O)Cc2cnn(C)c2)=c2cnc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1

Procedure:
A stock solution of Example 14e and N,N-diisopropylethylamine (0.11 M and 0.33 M in N,N-dimethylacetamide, respectively, 350 μL, 0.038 mmol Example 14e and 0.11 mmol N,N-diisopropylethylamine), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.13 M in N,N-dimethylacetamide, 350 μL, 0.046 mmol), and 2-(1-methyl-1H-pyrazol-4-yl)acetic acid (0.40 M in N,N-dimethylacetamide, 113 μL, 0.050 mmol) were aspirated from their respective source vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL per minute (10 minute residence time). Upon exiting the reactor, the reaction mixture was loaded directly into an injection loop and purified by reverse phase HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) to yield the title compound as an impure mixture. The material was dissolved in methanol (1 mL) and manually injected into the HPLC(C8, acetonitrile/water (0.1% ammonium acetate), 5-100%) give 0.0067 g (38%) of the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 8.49 (d, J=2.44 Hz, 1H), 8.45 (d, J=2.75 Hz, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.07 (s, 1H), 6.87 (m, 2H), 6.57 (m, 2H), 4.60 (m, 2H), 4.07 (s, 3H), 3.81 (s, 3H), 3.55 (s, 2H). MS (APCI+) m/z 484.1 (M+H)+.
Reaction SMILES: CC(C)=C[CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C[N+]1([O-])CC[O:22]CC1.[C:26]([OH:30])([CH3:29])([CH3:28])[CH3:27].C1COCC1.O>S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>[OH:22][CH:27]([C:26]([OH:30])([CH3:29])[CH3:28])[CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16]
Reactant: CC(C)=CCON1C(=O)c2ccccc2C1=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)O
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)C(O)CON1C(=O)c2ccccc2C1=O
Reaction time: 17 h

Procedure:
2-(3-Methyl-but-2-enyloxy)-isoindole-1,3-dione was dissolved in a t-butanol/THF/H2O solution (10 mL/3 mL/1 mL) and charged with N-methylmorpholine N-oxide (0.085 g, 0.73 mmol) and a catalytic amount of potassium osmate dihydrate. After stirring for 17 hours the reaction was diluted with a saturated solution of sodium metabisulfate and partitioned with ethyl acetate. The organic layer was washed twice with saturated solution of sodium metabisulfate, twice with saturated sodium chloride solution, collected and dried over Na2SO4, filtered and concentrated in vacuo affording 2-(2,3-dihydroxy-3-methyl-butoxy)-isoindole-1,3-dione as a clear oil, which was charged with dichloromethane (10 mL), 2,2-dimethoxypropane (0.12 mL, 0.75 mmol) and a catalytic amount of p-toluenesulfonic acid. After stirring for 17 hours, the reaction was concentrated in vacuo, and partitioned between ethyl acetate and water. The organic layer was washed twice with water, once with saturated sodium chloride solution, collected and dried over Na2SO4, filtered and concentrated in vacuo, affording 2-(2,2,5,5-tetramethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione as a light brown solid (0.158 g, 77.1%): 1H NMR (400 MHz; DMSO-d6) δ 7.82 s, (4H), 4.12-4.26 (m, 2H), 4.04-4.07 (m, 1H), 1.22 (s, 9H), 1.17 (s, 3H), 0.97 s(3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:41])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:41])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)cc1Cl
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To the suspension of 4-(3-chloro-4-fluoro-phenyl)-1H-indole (2.03 g, 8.26 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (99 mL) was added pyridinium tribromide (7.93 g, 24.79 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (40 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (1.39 g, 64%) as a tan solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Br[CH2:13][CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+].C[C:23]#[N:24]>>[CH3:11][O:10][C:9]1[C:2]([O:1][CH2:13][CH2:14][CH3:15])=[C:3]([CH:6]=[CH:7][CH:8]=1)[CH2:4][CH2:23][NH2:24]
Reactant: CC#N
Reactant: COc1cccc(C=O)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOc1c(CCN)cccc1OC
Temperature: 25 °C

Procedure:
A suspension of 2-hydroxy-3-methoxy-benzaldehyde (10.0 g, 65.6 mmol), 1-bromopropane (60 mL, 657 mmol) and K2CO3 (11.3 g, 82.1 mmol) in MeCN (250 mL) was heated to reflux for 12 h. The mixture was cooled to ambient temperature and the solution filtered. The filtrate was concentrated to give the title compound (12.9 g, quantitative) as light yellow oil: MS (ESI) m/e 195 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)N2C[C@H](O)C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cis-4-hydroxy-D-proline (0.308 g, 2.67 mmol) is dissolved in 16 mL of a 1:1 mixture of water and p-dioxane and then triethyl amine (0.819 mL, 5.89 mmol), 4-butoxyphenylsulfonyl chloride (0.700 g, 2.81 mmol), and 4-dimethylaminopyridine (0.033 g, 0.268 mmol) are added. The resulting solution is stirred at room temperature overnight. The reaction is then washed with sodium bicarbonate and extracted once with ether. The water layer is acidified with 1N HCl to pH=2 and extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, dried (MgSO4), filtered and evaporated to give the crude compound. Cl+ MS: m/z (rel intensity) 361 (M+ +H, 40).
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>CN(C=O)C>[C:16](=[O:17])([O:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C:16](=[O:17])[O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH:4]=[CH:3][CH:2]=1)[O:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)COC(=O)Cl
Reactant: Oc1cccc2cccc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)Oc1cccc2cccc(OC(=O)OCC(C)C)c12
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a round-bottom flask is charged naphthalene-1,8-diol (4.0 g, 25 mmol), and anhydrous DMF (50 ml). The flask is immersed in an ice-water bath, and 60% sodium hydride in mineral oil (2.4 g, 60 mmol) is added in portions. The mixture is stirred for an hour. Isobutyl chloroformate (8.2 g, 60 mmol) is added dropwise. After gradually warming to room temperature, the mixture is stirred overnight. The mixture is poured into ice-cold water and extracted with ether three times. The combined ether extracts are washed with water, then brine, and then dried over magnesium sulfate. After filtration, the filtrate is concentrated, and the residue is purified by flash column chromatography on silica gel to yield 2.8 g (31%) of the product as a light-grey solid. 1H NMR (400 MHz, CDCl3, ppm) δ 7.79 (dd, 2H, J=1.2, 8.0 Hz), 7.47 (dd, 2H, J=7.6, 8.0 Hz), 7.26 (dd, 2H, J=1.2, 7.6 Hz), 4.07 (d, 4H, J=6.8 Hz), 2.07 (m, 2H), 1.00 (d, 12 H, J=6.8 Hz).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([N:18]([CH2:36][CH3:37])[CH2:19][CH2:20][NH:21][C:22]1[N:23]=[N+:24]([O-:35])[C:25]2[CH:31]=[C:30]3[CH2:32][CH2:33][O:34][C:29]3=[CH:28][C:26]=2[N:27]=1)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[O-:35][N+:24]1[C:25]2[CH:31]=[C:30]3[CH2:32][CH2:33][O:34][C:29]3=[CH:28][C:26]=2[N+:27]([O-:4])=[C:22]([NH:21][CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:36][CH3:37])[N:23]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCN(CC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])OCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
H2O2 (70%, 0.38 mL, ca. 2.8 mmol) was added dropwise to a stirred solution of TFAA (1.1 mL, 2.8 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 209 (235 mg, 0.78 mmol) and TFA (0.13 mL, 1.7 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (3×25 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (5-10%) of MeOH/DCM, to give 1,4-dioxide 210 (95 mg, 38%) as a red solid: mp 187-190° C.; 1H NMR (CD3OD) δ 8.16 (t, J=1.7 Hz, 1H, H-9), 7.30 (s, 1H, H-5), 4.85 (t, J=8.4 Hz, 2H, H-7), 3.90-3.94 (m, 2H, CH2), 3.40-3.49 (m, 4H, H-8, CH2), 3.36 (q, J=7.3 Hz, 4H, CH2), 1.37 (t, J=7.3 Hz, 6H, CH3), NH not observed; 13C NMR δ 169.8, 151.5, 142.3, 135.5, 128.2, 119.0, 93.7, 75.6, 51.7, 49.0 (2), 37.3, 29.4, 9.1 (2); HRMS (FAB+) calcd for C15H22N5O3 (MH+) m/z 320.1723, found 320.1726.
Reaction SMILES: CN(C=O)C.F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>C(OCC)(=O)C.O>[N:25]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(-n2ccnc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 2.9 %

Procedure:
To a DMF (2.0 mL) solution of 4-fluoro-3-trifluoromethylbenzaldehyde (400 mg), potassium carbonate (414 mg) and imidazole (136 mg) were added one by one, and the reaction solution was agitated at 80° C. for 6 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate 3:1→ethyl acetate) and 13.7 mg of 4-(1H-imidazol-1-yl)-3-trifluoromethylbenzaldehyde was obtained. Next, malonic acid (11.0 mg) and piperidine (53.0 mg) were added to an ethanol (1.0 mL) solution of the obtained aldehyde compound (13.0 mg), and the reaction solution was refluxed for 5 hours. Pyridine (2.0 mL) and malonic acid (11.0 mg) were added to the reaction solution, and the reaction solution was refluxed for one and a half hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 15.0 mg of crude carboxylic acid was obtained by condensing under reduced pressure. By the same method as in Example 324, 10.7 mg of the title compound was obtained from the obtained carboxylic acid and 1-aminoindan. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([Cl:29])=[O:28]>>[ClH:29].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][C:27]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[O:28])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(N3CCN(CCN)CC3)c2c1
Reactant: O=C(Cl)c1cccs1
Product: COc1ccc2cccc(N3CCN(CCNC(=O)c4cccs4)CC3)c2c1
Product: Cl

Procedure:
This compound was prepared according to the process described in Example 1, Stage E, from 1-(7-methoxy-1-naphthyl)-4-(2-aminoethyl)piperazine and 2-thiophenecarbonyl chloride.
Reaction SMILES: [CH3:1][NH:2][CH2:3]C(O)=O.[CH2:7]=O.[C:9]([O:17][CH3:18])(=[O:16])/[CH:10]=[CH:11]\[C:12]([O:14][CH3:15])=[O:13].O>C1C=CC=CC=1>[CH3:15][O:14][C:12]([C@H:11]1[C@@H:10]([C:9]([O:17][CH3:18])=[O:16])[CH2:7][N:2]([CH3:3])[CH2:1]1)=[O:13]
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: C=O
Reactant: CNCC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)[C@H]1CN(C)C[C@H]1C(=O)OC
Yield: 36.9 %

Procedure:
A mixture of 89.0 gm (1.0 mole) N-methylglycine, 60.0 gm (2.0 mole) paraformaldehyde and 144 gm (1.0 mole) dimethyl maleate in 1 L of benzene were heated to reflux with constant water removal for about 5 hours. The reaction mixture was cooled to ambient and allowed to stand over night. The solution was decanted from the solid and the solid was washed with diethyl ether. The combined organic phases were extracted with 10% hydrochloric acid and then this aqueous phase was made basic with concentrated ammonium hydroxide. The now basic aqueous phase was extracted with dichloromethane and the organic extracts were then dried over sodium sulfate and concentrated in vacuo to give a yellow liquid. This material was fractionated through a Vigreaux column to give 74.25 gm of the desired compound, b.p.=119°-123° C. (8 mm Hg).
Reaction SMILES: [BH3:1].CSC.C1CCCCC=1.[F:11][CH2:12][CH:13]=[CH2:14].C[N+]([O-])(C)C.[CH3:20][C:21]([OH:27])([C:23]([CH3:26])([OH:25])[CH3:24])[CH3:22]>C(COC)OC>[CH3:24][C:23]1([CH3:26])[C:21]([CH3:22])([CH3:20])[O:27][B:1]([CH2:14][CH2:13][CH2:12][F:11])[O:25]1
Reactant: C=CCF
Reactant: CC(C)(O)C(C)(C)O
Reactant: B
Agent: C[N+](C)(C)[O-]
Solvent: COCCOC
Solvent: CSC
Solvent: C1=CCCCC1
Product: CC1(C)OB(CCCF)OC1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 35.5 %

Procedure:
2.5 ml (25 mmol) of borane-dimethyl sulphide (1:1) complex were dissolved in 50 ml of dimethoxyethane and the solution was cooled to 0° C. under nitrogen. 5.3 ml (52.5 mmol) of cyclohexene were then added. The solution was stirred at 0° C. for 15 minutes, then at room temperature for 1 hour and then cooled to -10° C. 1.6 g (27 mmol) of 3-fluoropropene were condensed and then added to the foregoing solution which was then stirred at room temperature under a dry ice condenser. After 1 hour the condenser was removed and stirring was continued for a further 1 hour. 3.9 g (52 mmol) of trimethylamine N-oxide were added and the solution was stirred for 1 hour. 3.1 g (26.3 mmol) of 2,3-dimethyl-2,3-butanediol were added and the solution was stirred for 16 hours. The solution was evaporated and the residue was distilled. The distillate boiling at 35-65° C./1mm Hg was collected and purified by chromatography on silica gel using diethyl ether/ hexane (1:9) for the elution to give 1.67 g of 4,4,5,5-tetramethyl-2-(3-fluoropropyl)-1,3,2-dioxaborolane as a colourless oil; 1H NMR (250 MHz, CDCl3) δ: 0.75-0.85 (m, 2H), 1.25 (s, 12H), 1.7-1.9 (m, 2H), 4.28 (t, 1H), 4.48 (t, 1H).