Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3]1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])[CH3:23].O>CN(C=O)C>[Si:25]([O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH:2]3[CH2:3][CH2:4][CH2:5]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1)([C:22]([CH3:24])([CH3:23])[CH3:21])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc2c(C3CCC3)n[nH]c2c1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c(C3CCC3)n[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyclobutylindazol-6-ol hydrochloride (6.45 g) which can be prepared according to the method described in Reference example 11, etc. and imidazole (5.039 g) were dissolved in DMF (100 mL; manufactured by Kanto Chemical Co., Inc.). Then, TBDPSCl (18.44 mL) was added and the mixture was stirred overnight at room temperature. To the reaction solution, water was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (9.93 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][CH2:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.[BH4-].[Na+]>CC(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:13][CH2:14][C:15]2[CH:29]=[CH:28][C:18]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CNCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 4-fluorobenzaldehyde (496 mg, 4.00 mmol) in a mixed solvent of CH2Cl2 (10 mL) and 2-propanol (2 mL) at rt was added tert-butyl 4-(aminomethyl)benzylcarbamate (945 mg, 4.00 mmol, Aldrich). The reaction mixture was stirred at rt overnight. The next morning, sodium borohydride (296 mg, 8.0 mmol) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was quenched by adding 3 mL of MeOH and 3 mL of saturated aq NaHCO3. The mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were dried, concentrated and purified by flash column chromatography on silica gel eluting with CH2Cl2/EtOAc to give the title compound (0.69 g, 48%) as a viscous material. MS (ESI): 345.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1I
Reactant: Clc1ccc2cc[nH]c2c1
Product: Cc1ccccc1-n1ccc2ccc(Cl)cc21

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and 1-iodo-2-methylbenzene: ESMS m/e: 241.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)([O-:5])=[O:4].[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O.C1(C)C=CC=CC=1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[N:11]([CH2:19][C:18]#[CH:17])[C:10]=2[CH:16]=1)([O-:5])=[O:4]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
While kept under N2, 0.81 g (20 mmol) of sodium hydride (60% dispersion in oil) was washed with 3 ml of pentanes and suspended in 20 ml of anhydrous dimethylformamide. While cooling with an ice/brine bath, 3.59 g (18.5 mmol) of 6-nitro-2H-1,4-benzoxazin-3(4H)-one was added through a dry powder funnel (exotherm of about 5° C.). An additional 10 ml of DMF was added and the mixture was stirred at 0° C. for 30 minutes. There was then added 2.06 ml (18.5 mmol) of an 80% solution of propargyl bromide in toluene and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was poured into 50 ml of water and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with water (2×50 ml) and dried (MgSO4). The solvent was removed in vacuo to yield 6-nitro-4-propargyl-2H-1,4 -benzoxazin-3(4H)-one as a yellow solid, 4 g (93% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].O.[N-:30]=[N+:31]=[N-:32].[Na+]>S(Cl)(Cl)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([N:30]=[N+:31]=[N-:32])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (105 mg, 269 μmol) was dissolved in thionyl chloride (5 mL) and was stirred at 65° C. for 1 h. The reaction mixture was concentrated before it was dissolved in DCM (3 mL); to this was added tetrabutylammonium bromide (8 mg, 27 μmol), water (269 μl, 269 μmol), and sodium azide (21.0 mg, 323 μmol) at 0° C. before it was stirred for 2 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoyl azide. MS (ESI) m/z: Calculated: 415.1; Observed: 416.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:13]1[N:12]2[CH:16]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1CCN(Cc2cn3c(O)nc(-c4ccc(Cl)cc4Cl)cc3n2)CC1
Product: CN1CCN(Cc2cn3c(Cl)nc(-c4ccc(Cl)cc4Cl)cc3n2)CC1

Procedure:
In analogy to Example 95A, 42 mg (17% of theory) of the product are obtained from 225 mg (0.49 mmol) of 7-(2,4-dichlorophenyl)-2-[(4-methylpiperazin-1-yl)methyl]imidazo[1,2-c]-pyrimidin-5-ol (Example 94A) by reaction with phosphoryl chloride.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])N2C[CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1)=[O:2].[C-:35]#[N:36].[Na+].[CH3:38][OH:39]>O=[Mn]=O>[CH3:38][O:39][C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:36]2[CH2:35][CH2:17][CH2:16][CH2:15]3)=[CH:33][CH:34]=1)=[O:2]
Reactant: [C-]#N
Reactant: O=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Reactant: CO
Agent: O=[Mn]=O
Agent: [Na+]
Product: COC(=O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[4-(2-formylphenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.206 g) in MeOH (20 mL) was added NaCN (0.204 g), ACOH (0.086 mL) and MnO2 (activated, 1.84 g) and the mixture was stirred overnight at room temperature. The inorganics were removed by filtration through Celite and the filtrate was evaporated. The residue was dissolved in EtOAc and washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/2) afforded the titled compound (0.161 g). It was converted to the HCl salt. MS (m/z) 545 (M30 +Na), 523 (MH+)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2CO)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O1CCCC1>O>[C:25]1([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:20][Cl:24])(=[O:33])=[O:32])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(c1ccccc1)c1ccccc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 60 h
Yield: 84.8 %

Procedure:
Triphenylphosphine (4.08 g, 15.5 mmol), carbon tetrachloride (7.0 mL, 73 mmol), (2-benzenesulfonyl-phenyl)-methanol (1.90 g, 7.65 mmol) and tetrahydrofuran (40 mL) were combined and heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, then stirred at room temperature for 60 hours. The reaction mixture was diluted with water, then extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated to give the crude product as an oily solid. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (0%-15% ethyl acetate in hexanes) afforded 1.73 g (85%) of 2-(benzenesulfonyl)benzyl chloride as an off-white, crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.14 (d, J=7.8 Hz, 1 H), 7.93 (d, J=7.2 Hz, 2 H), 7.56-7.82 (m, 6 H), 5.07 (s, 2 H). HRMS (EI+) cald. for C13H11ClO2S [M+] 266.0168, obsd. 266.0168.
Reaction SMILES: [CH:1]1([NH:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29]1([CH2:35][S:36](Cl)(=[O:38])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[S:36]([CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:38])=[O:37])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCN(c2ccc(CNC3CCC3)cc2)CC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(CN(C3CCC3)S(=O)(=O)Cc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
To a solution of 1-(4-(4-((cyclobutylamino)methyl)phenyl)piperazin-1-yl)ethanone (185 mg, 0.64 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.18 mL, 1.29 mmol), followed by phenylmethanesulfonyl chloride (185 mg, 0.96 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to yield 62 mg of N-[4-(4-Acetyl-piperazin-1-yl)-benzyl]-N-cyclobutyl-C-phenyl-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.46-7.29 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 4.36 (s, 2H), 4.18 (s, 2H), 4.14-3.98 (m, 1H), 3.63-3.48 (m, 4H), 3.18-3.10 (m, 2H), 3.10-3.00 (m, 2H), 2.03 (s, 3H), 2.01-1.89 (m, 2H), 1.89-1.72 (m, 2H), 1.54-1.15 (m, 2H); LCMS (m/z) ES+ 442.2 [M+1]+.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:31]=[C:30](C(F)(F)F)[CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22].FC(F)(F)[C:38]1[CH:39]=[C:40]([S:48](Cl)(=[O:50])=[O:49])[CH:41]=[C:42](C(F)(F)F)[CH:43]=1>>[CH:1]([OH:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([S:48]([NH:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O-:23])=[O:22])(=[O:49])=[O:50])[CH2:41][CH2:42][CH2:43][CH2:38][CH2:39][CH2:1][CH3:2]
Reactant: Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: OC(c1ccccc1)c1ccccc1
Product: CCCCCCCCS(=O)(=O)Nc1ccccc1Oc1ccccc1C(=O)[O-]

Procedure:
Following the procedure of Example 1(e) except substituting benzhydrol 2-(2-aminophenoxy)benzoate for benzhydrol 2-(2-amino-4-trifluoromethylphenoxy)benzoate and substituting 1-octanesulfonyl chloride for 3,5-bis(trifluoromethyl)benzenesulfonyl chloride, the title compound was obtained as a white solid. 1H NMR (250 MHz, CDCl3) δ8.01 (dd, 1H), 7.64 (dd, 1H), 7.47-7.52 (m, 2H), 7.00-7.33 (m, 14H), 6.85 (dd, 1H), 6.53 (dd, 1H), 2.88-2.95 (m, 2H), 1.65-1.69 (m, 2H), 1.18-1.25 (m, 10H), 0.85 (t, 3H).
Reaction SMILES: [PH2](=O)[O-].NC(N)=S.[CH3:8][P:9]([O:14][CH2:15][CH2:16][Cl:17])[O:10]CCCl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]=O)=[CH:21][CH:20]=1.[C:28]1([NH:34][C:35]([NH2:37])=[S:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35](=[S:36])[NH:37][CH:26]([P:9]([CH3:8])(=[O:10])[O:14][CH2:15][CH2:16][Cl:17])[CH2:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CP(OCCCl)OCCCl
Reactant: O=CCc1ccc(Cl)cc1
Agent: NC(N)=S
Agent: O=[PH2][O-]
Product: CP(=O)(OCCCl)C(Cc1ccc(Cl)cc1)NC(=S)Nc1ccccc1

Procedure:
This example shows the preparation of a phosphinate compound, i.e., a compound having two P--C bonds. It also shows the use of a thiourea as a reactant. When equimolar quantities of bis(2-chloroethyl) methylphosphonite, p-chlorophenylacetaldehyde, and phenylthiourea are warmed at 90°-110° C for 1 hour, 2-chloroethyl [1-(3-phenylthioureido)-2-(p-chlorophenyl) ethyl]methylphosphinate is formed. Hydrolysis gives the corresponding phosphinic acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.[CH2:14](I)[CH3:15].CN(C)C=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:14][CH3:15])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: CC(=O)Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
820 mg (20.5 mmol, 1.1 eq) of 60% sodium hydride are added to a solution of 4.0 g (18.7 mmol, 1 eq) of N-(3-bromophenyl)acetamide and 1.80 mL (22.4 mmol, 1.2 eq) of ethyl iodide in 15 ml of tetrahydrofuran in the presence of 1.5 ml of dimethylformamide. The reaction medium is stirred at room temperature for 12 hours and then hydrolyzed with water and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the N-(3-bromophenyl)-N-ethylacetamide obtained in oil form is used in the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20]C(C)C)=[O:19].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>O1CCCC1.CCOCC>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][S:8][C:6]2[NH:7][C:2]([CH3:1])=[C:3]([C:18]([OH:20])=[O:19])[CH:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:5]=2)=[CH:28][CH:27]=1
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)NC(=S)N1
Reactant: COc1ccc(CCl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CSC2=NC(c3cccc([N+](=O)[O-])c3)C(C(=O)O)=C(C)N2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(-)-1,2,3,4-Tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, 1-methylethyl ester (2.6 mmol, 884 mg) was dissolved in dry tetrahydrofuran and cooled to 0° C. 4-Methoxybenzyl chloride (1.1 eq, 32.9 mmol, 393 μl) was added dropwise. After the addition was complete, the bath was removed and the reaction stirred at room temperature for two hours. The mixture was then heated at 65° C. for 16 hours. TLC 35:65:acetone:hexane showed an incomplete reaction, so additional 4-methoxybenzyl chloride (1.1 eq, 1.3 mmol, 393 μl) was added to the mixture. After 7 hours at 65° C., the mixture was allowed to come to room temperature and diluted with ether. As the mixture cooled to 0° C., a white solid formed. The solid was collected by suction filtration, washed with ether, and dried to afford 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylether ester hydrochloride, 636 mg (49%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[CH:12]([C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)=O.[CH2:25]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34](O)[CH:35]=2)[C:30](C)=CC1(C)C)[CH3:26]>CO>[CH2:1]([NH:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]2[C:12]([C:14]3[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)=[C:33]3[C:34]([O:11][C:6]=2[CH:5]=1)=[CH:35][C:36](=[N:27][CH2:25][CH3:26])[C:31]([CH3:30])=[CH:32]3)[CH3:2]
Reactant: CCNc1cc(O)ccc1C
Reactant: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Solvent: CO
Product: CCN=c1cc2oc3cc(NCC)c(C)cc3c(-c3ccc(OCC(=O)O)cc3)c-2cc1C
Yield: 12 %

Procedure:
Dye 4 (shown below) was prepared using the procedure described in Example 4 except that 3-(ethylamino)-4-methylphenol and 2-(4-formylphenoxy)acetic acid substituted for 1-ethyl-2,2,4-trimethyl-1,2-dihydroquinolin-7-ol and 2-(4-formylphenoxy)acetic acid. Yield: 12%. λabs=525 nm (in methanol), λem=540 nm (in methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:10])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A mixture of 4-fluorophenylacetyl chloride (4.91 g, 24.3 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (3.50 g, 24.3 mmol) and DIEA (5.84 g, 49.8 mmol) in DCM (30 mL) was stirred for 1 h at 0° C., then warmed to RT for 2 h. The solution was diluted with DCM, washed with 0.1 N HCl and brine, dried over Na2SO4 and evaporated to dryness. The resulting orange solid was suspended in EtOH (100 mL) and refluxed for 2 hours. The solution was evaporated and the resulting orange oil was left in the freezer overnight to give a yellow solid. The crude solid was recrystallized from EtOH to afford ethyl 4-(4-fluorophenyl)-3-oxobutanoate (5.3 g, 86.8% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6]C(S(O)(=O)=O)=[CH:4][CH:3]=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13].C(OC1C=CC(N)=C(O)C=1)(=O)C.CC(C(=O)C)C(=O)C>>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:7]([CH3:6])=[C:2]([CH3:1])[C:3]([CH3:4])=[N:23]2)=[C:18]([OH:24])[CH:17]=1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)Oc1ccc(NN)c(O)c1
Agent: CC(=O)C(C)C(C)=O
Agent: CC(=O)Oc1ccc(N)c(O)c1
Product: CC(=O)Oc1ccc(-n2nc(C)c(C)c2C)c(O)c1
Yield: 52.2 %

Procedure:
230 mg of the title compound was prepared in a manner similar to Example 54b) by using 4-hydrazinyl-3-hydroxyphenyl acetate 4-methylbenzenesulfonate (0.6 g), which was prepared from 4-amino-3-hydroxyphenyl acetate (1.0 g) in a manner similar to Example 54a), and 3-methylpentane-2,4-dione (1.0 g).
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].P.[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:6]([O:14][P:1]([Cl:4])[Cl:2])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: ClP(Cl)Cl
Reactant: CCCCCCCCO
Agent: P
Product: CCCCCCCCOP(Cl)Cl
Temperature: 0 °C

Procedure:
Freshly distilled phosphorus trichloride (45.6 g, 0.338 mole) was charged into a four-necked round bottom flask equipped with a mechanical stirrer, an addition funnel, a thermometer, and a reflux condenser itself topped with a discharge tube. The discharge tube led to an aqueous sodium hydroxide trap for absorption of hydrogen chloride that evolves from the reaction. After cooling the reaction vessel to 0° C. with continual purging of dry nitrogen, anhydrous octanol (22 g, 0.168 mole) was added dropwise to the reaction mixture. When the addition of the octanol was complete, the reaction mixture was allowed to warm gradually up to room temperature and was then poured into a dry distillation flask. The material was distilled with a bath temperature of 80-85° C. and using a water pump vacuum to remove residual hydrogen chloride and excess phosphorus trichloride. The residue was then fractionated at 8 mm Hg to yield the product at 113-130° C. in 69% conversion. The phosphorus-31 NMR showed a peak at 176 ppm. The refractive index at 21.5° C. was 1.4682.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:23]1([N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)[CH2:26][CH2:25][CH2:24]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccccc2N2CCN(C3CCC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (20 mg, 0.067 mmol) produced in Example (8b) in tetrahydrofuran (1 mL) were added cyclobutanone (7.0 mg, 0.1 mmol), sodium triacetoxyborohydride (28 mg, 0.13 mmol) and acetic acid (4 mg, 0.067 mmol) in that order, followed by stirring for 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-cyclobutyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine. The obtained compound was dissolved in ethyl acetate, and a 4N solution of hydrogen chloride in ethyl acetate (0.025 mL, 0.100 mmol) was added. The solution was concentrated, and hexane was added to the obtained residue to produce a solid. The solid was triturated by sonication and the supernatant hexane solution was removed. The solid residue was dried under reduced pressure to give 17.6 mg of the title compound as a white solid.