Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].[C:27]1([CH3:37])[C:28]([S:33]([Cl:36])(=[O:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>>[ClH:36].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:37])(=[O:35])=[O:34])=[C:3]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(C)(=O)=O)c2)CC1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(N2CCCNCC2)cc1NS(C)(=O)=O
Product: Cl

Procedure:
The compound was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}methanesulfonamide and o-toluenesulfonylchloride (87 mg, 0.455 mmol) to give before Boc-deprotection 175 mg of a purple solid. M+ 1 439.2 Calcd 438.14.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>CO.C(OCC)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Fc1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 113.5 %

Procedure:
To the product from step 1 (271 mg, 0.699 mmol) in methanol (3 mL) was added 1M HCl in diethyl ether (15 mL) and the resulting mixture was stirred at rt for 7 h. The solvent was removed in vacuo to obtain the product as a solid (228 mg, 99%): MS; m/z 288 (M+H): LCMS (UV) 98%. 1H NMR (400 MHz, DMSO-d6) δ 1.70-1.76 (m, 1H), 1.89-1.99 (m, 2H), 2.01-2.14 (m, 1H), 3.18-3.23 (m, 2H), 3.87-3.90 (m, 1H), 4.12-4.16 (dd, 1H J1=8.4 Hz, J2=10.8 Hz), 4.21-4.25 (dd, 1H J1=4 Hz, J2=10.8 Hz), 6.96-6.99 (m, 2H), 7.014-7.016 (m, 4H), 7.17-7.22 (m, 2H), 9.1 (s, 1H), 9.7 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([CH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)O)[CH:20]=[CH:19]2>>[OH:6][C:5]1[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3](=[O:7])[C:4]=1[CH:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc2cc(C(O)c3ccccc3)ccc2c1
Reactant: CC1(c2ccccc2)C(=O)CC1=O
Product: COc1ccc2cc(C(C3=C(O)C(C)(c4ccccc4)C3=O)c3ccccc3)ccc2c1

Procedure:
Using general procedure D, 2-methyl-2-phenyl-cyclobutane-1,3-dione (Lit. 1) was reacted with (6-methoxy-naphthalen-2-yl)-phenyl-methanol to give the title compound as a colorless solid. MS: 419.3 ([M−H]−).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:21]=4)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[CH3:33][N+:27]1([CH2:26][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:17]([C:13]3[CH2:12][CH2:11][C:10]4[C:15](=[CH:16][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][CH:9]=4)[CH:14]=3)=[O:18])=[CH:25][CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In DMF (3 ml) was dissolved 7-phenyl-N-[4-(piperidinomethyl)phenyl]-3,4-dihydronaphthalene-2-carboxamide (240 mg), and to the mixture was added methyl iodide (106 μl). The mixture was stirred at room temperature for 60 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-methyl-1-[4-(7-phenyl-3,4-dihydro-naphthalene-2-carboxamido)benzyl]piperidinium iodide (Compound 5) (247 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([N:25]3[CH2:26][CH2:27][C:22]([CH3:28])([CH3:21])[CH2:23][CH2:24]3)=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CC1(C)CCNCC1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCN(C(=O)c2ccc(C3CC3)c(Cc3ccc(F)cc3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with 4,4-dimethyl-piperidine (4045-30-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=367.5 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25]CC)=[O:24])[N:20]=[N:19][N:18]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1.CO.[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[N:19][N:18]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnnc1-c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cn1nnnc1-c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-1H-tetrazol-1-yl)acetate (Isomer A) from Step 7 (0.067 g, 0,132 mmol) in THF (2 mL) and MeOH (2 mL) was added 1 N NaOH (2 mL). After approximately 2 h, ethyl acetate and 1 N HCl were added to the reaction mixture. The organic phase was separated, dried over sodium sulfate and evaporated to give the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14].[C:15](=O)([O:18]C)[O:16][CH3:17].O>O1CCCC1.C(OCC)(=O)C>[CH3:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)OC
Reactant: Cc1ccncc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Nc1cnccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
At about 0° C., potassium tert-butoxide (47 g, 420 mmol, 3.00 equiv.) was added in several batches to a solution of 4-methylpyridin-3-amine (15 g, 139 mmol, 1.00 equiv.) in tetrahydrofuran (400 mL). After stifling the solution for about 30 minutes, dimethyl carbonate (18.8 g, 209 mmol, 1.50 equiv.) was then added. The solution was stirred at ambient temperature for about 16 hours and then water (100 mL) was added. Following standard extractive workup with ethyl acetate (3×200 mL), the crude product was purified by re-crystallization from ethyl acetate/petroleum ether (1:1) to give the title product as a pale yellow solid (17 g; yield=74%). LC-MS: m/z=167 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:37])=[C:21]([CH:36]=1)[CH2:22][N:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1)[CH2:24][CH3:25]>CN(C=O)C.O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:37][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[C:21]([CH:36]=1)[CH2:22][N:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1)[CH2:24][CH3:25]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccncc1)c1ccc(C(=O)OC)cn1
Reaction time: 24 h
Yield: 64.5 %

Procedure:
A solution of 4-chloromethylpyridine hydrochloride (0.12 g, 0.73 mmol) in DMF (3 ml) was treated with potassium carbonate (0.29 g, 2.10 mmol). A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (0.26 g, 0.71 mmol) in DMF (4 ml) was added. The reaction was stirred for 24 hours and then the reaction was diluted with water and extracted with ethyl acetate (×3). The organic phases were combined and washed with water and brine once, dried (MgSO4) and evaporated. Chromatography eluant: ethyl acetate/hexane gave methyl 2-[N-(5-bromo-2-(4-pyridylmethoxy)benzyl)-N-ethylamino]pyridine-5-carboxylate as a white solid (0.209 g, 65%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)cc(F)c3)c(=O)n12
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solutions of 7-(1-azidoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.15 g, 0.43 mmol) (1 st peak from chiral separation) in tetrahydrofuran (2 mL) and water (0.5 mL) were added 1.00 M of trimethylphosphine in tetrahydrofuran (0.52 mL, 0.52 mmol) at room temperature and the mixtures were stirred at room temperature for 1 hour. To the mixture was added EtOAc and the mixture was extracted with aqueous 1N HCl solution (three times). The combined extracts were neutralized with solid Na2CO3 and extracted with dichloromethane (two times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the desired product (134 mg, 96.6%). LCMS calculated for C15H14F2N3OS (M+H)+: m/z=322.1. Found: 322.0.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C=O.[C:7](OC(=O)C)(=O)C.[CH:14]([C:17]1[NH:18][C:19](=[O:27])[C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:16])[CH3:15]>>[CH3:2][N:3]([CH2:7][C:26]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:27])[NH:18][C:17]=1[CH:14]([CH3:16])[CH3:15])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: CNC
Reactant: CC(C)c1cc2ccccc2c(=O)[nH]1
Agent: C=O
Agent: Cl
Product: CC(C)c1[nH]c(=O)c2ccccc2c1CN(C)C
Temperature: 60 °C

Procedure:
While heating a mixture of dimethylamine hydrochloride (2.45 g) and 37% aqueous formalin solution (2.43 g) to 50° C., acetic anhydride (9.4 mL) was added dropwise thereto slowly. After the completion of the dropwise addition, the mixture was heated at 60° C. for 30 min. 3-Isopropyl-2H-isoquinolin-1-one (1.87 g) was added, and the mixture was stirred with heating at 80-100° C. for 1 day. After the completion of the reaction, the solvent was evaporated. The obtained residue was dissolved in 1N hydrochloric acid, and the mixture was washed with chloroform. Aqueous potassium carbonate solution was added to alkalify the aqueous layer, and the mixture was extracted with chloroform, and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 4-dimethylaminomethyl-3-isopropyl-2H-isoquinolin-1-one (0.39 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:21].C1C(=O)N([Cl:29])C(=O)C1>C(#N)C>[Cl:29][C:9]1[C:8]2[N:7]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:6]=[CH:5][C:4]=2[C:3]([NH2:21])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)ccc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N)c(C)cc(Cl)c32)cc1
Temperature: 50 °C

Procedure:
To a solution of 5-methyl-1-tosyl-1H-indol-4-amine (0.52 g, 1.731 mmol) in acetonitrile (17.31 mL) was added NCS (0.231 g, 1.731 mmol), and the mixture was stirred at 50° C. After 2 hours the reaction was cooled to room temperature, quenched with sat. aq. NaHCO3, and with sat. sodium thiosulfate. The layers were separated and the aqueous layer extracted with EtOAc (twice), dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 335.0 (M+H).
Reaction SMILES: [Na].[OH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:9][O:10][C:11]1[CH:32]=[CH:31][C:14]([C:15](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.[N+:33]([C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)([O-:35])=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:32]=[CH:31][C:14]([C:15]([O:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][C:39]2[CH:40]=[CH:41][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)=[O:7])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(O)CCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: c1ccncc1
Product: COc1ccc(C(OCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
The sodium salt of 4-hydroxybutyric acid (1.26 g; 10 mmol) is dissolved in anhydrous pyridine (30 ml), and 4,4′-dimethoxytrityl chloride (3.39 g; 3.05 mmol) is added. After 16 hours, 4-nitrophenol (1.39 g; 10 mmol) and N,N′-dicyclohexylcarbodiimide (2.06 g; 10 mmol) are added, and the mixture is stirred at 22° C. for a further 48 hours. The precipitated dicyclohexylurea is filtered off and washed with dichloromethane. The filtrate is concentrated and the resulting residue is coevaporated twice with toluene. The residue is purified on a silica gel column (10-50% ethyl acetate and 1% triethylamine in petroleum ether). The desired compound is obtained in the form of a pale yellowish-colored oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([OH:12])[C:3]=1[C:4]([O-:6])=[O:5].N1C=CC=C[CH:14]=1.[F:19][C:20]([F:26])([F:25])[S:21](O)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])[C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C([O-])c1c(O)cc(Cl)cc1Cl
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cc(Cl)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of 2,4-dichloro-6-hydroxybenzoate (4.64 g, 20.99 mmol) and pyridine (1.87 mL, 23.09 mmol) in 100 mL CH2Cl2 was cooled to 0° C. Trifluoromethanesulfonic acid (4.94 mL, 29.39 mmol) was added, and the solution was stirred for 2 h. The reaction mixture was washed with aqueous sodium bicarbonate, aqueous copper sulfate and brine, dried over Na2SO4, filtered and concentrated to provide methyl 2,4-dichloro-6-{[(trifluoromethyl)sulfonyl]oxy}-benzoate that gave proton NMR spectra consistent with theory.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].I[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH3:21]
Reactant: COC1CN(C(=O)c2ccc([N+](=O)[O-])c(O)c2)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CC(OC)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of (3-hydroxy-4-nitrophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 115, 250 mg, 1.007 mmol), iodoethane (185 mg, 1.208 mmol) and potassium carbonate (278 mg, 2.014 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate diluted with ethyl acetate (60 mL). The organic phase was washed with water (20 mL×2), brine (20 mL) and dried over sodium sulphate. The solvent was concentrated in vacuo and the residue purified by silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as a yellow powder (230 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 85 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 85%). 1H NMR (200 MHz, CDCl3): δ 3.17-3.20 (m, 4H), 3.77-3.80 (m, 4H), 4.13 (s, 3H), 6.97-7.09 (m, 4H), 7.24-7.41 (m, 3H), 7.81-7.82 (m, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:17][C:18]([F:21])([F:20])[F:19])C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:15][C:13]1[C:12]([Cl:16])=[CH:11][C:10]2[N:6]([CH2:5][CH2:4][OH:3])[C:7]([CH2:17][C:18]([F:19])([F:20])[F:21])=[N:8][C:9]=2[CH:14]=1
Reactant: CCOC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCCn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Reaction time: 1 h

Procedure:
To [5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzimidazol-1-yl]-acetic acid ethyl ester (915 mg) in toluene (20 mL) at −78° C. was added DiBAl-H (3.43 mls of 1.5 M in toluene). The resulting mixture was stirred for 1 hour. The reaction mixture was quenched with Rochelle's salt (aq), extracted with EtOAc, and dried over Na2SO4. The extracts were concentrated to a toluene solution and ethanol (10 mL) was added. To the resulting solution was added NaBH4 (533 mg). The resulting mixture was stirred for 5 hour. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (15%-60% EtOAc/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1.[CH2:14]([Cl:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl.C(#N)C>C(Cl)(Cl)Cl.C(O)C>[ClH:22].[CH2:14]([NH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Reactant: CCCCCCCCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC#N
Product: CCCCCCCCNC1CCc2c(C)cc(C)c(O)c21
Reaction time: 4 h
Yield: 15.1 %

Procedure:
To a solution containing 1.77 g of 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene and 2 ml of trethylamine in 100 ml of chloroform was added dropwise 2.23 g of octyl chloride at room temperature. Then the reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was washed with a diluted hydrochloric acid, water, an aqueous solution saturated with sodium bicarbonate, water and an aqueous solution saturated with sodium chloride in this order, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the residue thus obtained was dissolved in ethanol, tna an ethanol saturated with hydrogen chloride gas was added thereto form a hydrochlodide. Recrysttallized form acetonitrile to obtain 0.49 g of 2,3-dihydro-1-octylamino-4,6-dimethyl-7-hydroxy-1H-indene hydrochloride. Colorless needle-like crystals. Melting point: 120°-121° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:21](O)[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:23]=1[F:30])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(O)c1cc(F)c(F)cc1F
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1cc(F)c(F)cc1F
Yield: 79.9 %

Procedure:
In accordance with the method described in Example 6, except that 43.94 g (3S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)butyrate and an equal amount of anhydrous ethanol were used to replace (3S)-3-(tert-butoxycarbonylamino)-4-hydroxy-4-(2,4,5-trifluorophenyl)n-butyl ester and methanol respectively, 33.83 g (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyrate (yield: 77%) was obtained using the same method.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10](OCC)OCC)[CH:3]=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:10]=[CH:9][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(COc1cccc(Br)c1)OCC
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc2ccoc2c1
Yield: 72.9 %

Procedure:
To a solution of 1-bromo-3-(2,2-diethoxyethoxy)benzene (2.3 g, 8.35 mmol) in toluene (28 mL), was added PPA (5.0 mL) and refluxed for overnight. The reaction solution was added water at room temperature, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica-gel column chromatography (hexane). The title compound (1.2 g (yield 68%, mixture with 7-bromobenzofuran)) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH3:17]C[O-].[Na+].[N:21]1[CH:26]=CC=NN=1>CCO.N1C=CC=NN=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:16])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:17][NH:21][CH:26]=2)=[CH:6][CH:7]=1
Reactant: c1cnnnc1
Reactant: CC[O-]
Reactant: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 85 °C
Yield: 83 %

Procedure:
To a solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (4.6 g, 21 mmol) in absolute EtOH (45 mL) was added NaOEt solution (21% NaOEt solution in EtOH, 7.7 mL) and triazine (1.67 g, 21 mmol). The resulting mixture was heated to 85° C. for 1.5 h, cooled to room temperature and treated with an additional portion of triazine (0.08 g, 1 mmol) and NaOEt solution (21% NaOEt solution in EtOH, 0.4 mL). The reaction mixture was heated for an additional hour and concentrated in vacuo. The residue was treated with 1N HCl until the pH of the reaction was about 2. The precipitate was collected to give the desired ester intermediate, ethyl 5-(4-fluorophenyl )-4-oxo-1,4-dihydropyridine-3-carboxylate (4.5 g, 83%) as a yellow solid. MS (ESI+) m/z 262 (M+H)+.