Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([CH2:15][CH3:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH3:19])=[C:4]([F:22])[CH:3]=1.O([Si:31]([CH3:34])([CH3:33])[CH3:32])S(C(F)(F)F)(=O)=O.C(N(CC)CC)C>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]([C:12]([O:14][Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH2:13])=[C:10]([CH2:15][CH3:16])[N:9]=[C:8]2[CH2:17][CH2:18][CH3:19])=[C:4]([F:22])[CH:3]=1
Reactant: CCCc1nc(CC)c(C(C)=O)n1Cc1ccc(Br)cc1F
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)c1c(CC)nc(CCC)n1Cc1ccc(Br)cc1F
Temperature: 22 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2.50 g (6.81 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-acetyl-1H-imidazole (67 R1 =2-F, R2 =4-Br, n=0; prepared using the procedures of Example 3, Parts A and B) in 80 mL anhydrous THF was added 7.59 mL trimethylsilyl triflate (40.8 mmol) under nitrogen at 22° C., followed by 11.38 mL (81.9 mmol) triethylamine. The mixture was stirred at 22° C. for 2.5 hours and then diluted with 100 mL of anhydrous ethyl ether and quenched with 10 mL of saturated NaHCO3 solution. The organic layer was washed with saturated NaHCO3 solution, dried over Na2SO4, and filtered. Solvents were then removed under reduced pressure yield 2.69 g (90%) of the title compound as a brown oil, which was used without further purification. 1H NMR (300 MHz, CDCl3): δ 0.14 (s, 9H); 0.84 (t, 3H); 1.16 (t, 3H); 1.68 (m, 2H); 2.41 (t, 2H); 2.56 (q, 2H); 4.30 (s, 1H); 4.43 (s, 1H); 5.03 (s, 2H); 6.44 (t, 1H); 7.10 (m, 2H). ##STR103##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([Cl:11])=[C:6]([OH:12])[CH:5]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:14])[C:7]([Cl:11])=[C:6]([OH:12])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(Cl)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.9 g (19.3 mmol) of 4-Chloro-3,5-dihydroxy-benzoic acid methyl ester was dissolved in 250 ml of DMF and treated at 0° C. with 8.6 g (62 mmol) of potassium carbonate and 2.72 g (19.2 mmol) of iodomethane. The reaction solution was stirred at RT for 16 h. The solvent was removed under reduced pressure, the residue was taken-up in ethyl acetate and this solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with sodium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (5/1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Cl:10][CH2:11][C:12](OCC)(OCC)OCC>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9][C:12]([CH2:11][Cl:10])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CCO
Product: ClCc1nc2cc(Cl)ccc2s1
Temperature: 60 °C
Yield: 81.1 %

Procedure:
0.966 g of 2-amino-4-chloro-benzenethiol was dissolved in 10 ml of abs. ethanol. 1.44 g of 2-chloro-1,1,1-triethoxy-ethane were added and the reaction was heated at 60° C. overnight. The reaction mixture was then concentrated in vacuo, dissolved in diethyl ether and the organic phase was washed once each with 5% aqueous hydrochloric acid, followed by water and 10% aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica with heptanes/dichloromethane afforded 1.071 g of 5-chloro-2-chloromethyl benzothiazole as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1.[CH3:35][O:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:35][O:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([C:2]2[CH:7]=[C:6]([C:8]([N:10]3[CH2:14][CH2:13][CH:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH2:11]3)=[O:9])[CH:5]=[CH:4][C:3]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH:42]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Br)c1)N1CCC(c2cccnc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cncc(-c2cc(C(=O)N3CCC(c4cccnc4)C3)ccc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 125 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.7 mg, 0.019 mmol) was added to a solution of 3b (51.0 mg, 0.094 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (24.3 mg, 0.103 mmol) and sodium carbonate (94.0 μL, of a 2.0 M aqueous solution, 0.188 mmol) in EtOH:toluene (1.25 mL of an 80:20 mixture, respectively) at rt. The resulting solution was heated to 125° C. in a sealed microwave vial for 12 min. After cooling to rt, the reaction mixture was filtered through a short column of Celite®, eluting with EtOAc. The filtrate was washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions afforded the title compound 3c. m/z (ES) 572 (MH)+.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@@H:11]2[N:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C@H:12]2[CH2:13][S:14][C:15](=[O:16])[C@H:11]2[N:10]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1SC[C@H]2[C@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.1 %

Procedure:
In 1 ml of chloroform was dissolved 100 mg of (3aR,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione, 0.5 ml of pyridine was added to the solution, and the resulting mixture was stirred at room temperature for 23 hours. The reaction mixture was successively washed with 2M hydrochloric acid, water, a saturated sodium bicarbonate solution, and saturated brine. The organic layer was dried and then concentrated. By adding isopropyl ether, precipitated crystal was collected by filtration to give 75.1 mg of (3aS,6aR)-1,3-dibenzyl-hexahydro-4H-thieno[3,4-d]imidazol-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:6]=1[CH3:7]>CCO.[Pt]>[CH3:1][C@@H:2]1[C@H:6]([CH3:7])[N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C@H:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:3]1
Reactant: CCOC(=O)c1cc(C)c(C)n1C(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H](C)[C@H](C)N1C(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
To a solution of 1-tert-butyl 2-ethyl 4,5-dimethyl-1H-pyrrole-1,2-dicarboxylate (4.016 g, 15.02 mmol) in EtOH (100 mL) was added Platinum on carbon (5%, 0.58 g). The slurry was stirred under an atmosphere of hydrogen (1 atm) for 3 days. The slurry was filtered through celite and washed with MeOH. The filtrate was concentrated and the crude was purified by column chromatography (SiO2, 5-10-20% EtOAc/Hexanes) to provide rel-(2S,4S,5S)-1-tert-butyl 2-ethyl 4,5-dimethylpyrrolidine-1,2-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:31]1COC[CH2:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH2:31][CH3:32])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (650 mg, 2.07 mmol) in THF (2 mL) at −78° C. was added lithium hexamethyldisilazide (LiHMDS) in THF (3.1 mL, 1.0 M in THF, 3.1 mmol) dropwise over 15 min. The resulting mixture was allowed to stir at −78° C. for 30 min before the addition of Etl (650 mg, 8.75 mmol). The reaction mixture was stirred at −78° C. for 2.5 h before it was allowed to warm up to room temperature for 15 min. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and EtOAc (25 mL, 1:1, v/v). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography to give 9-(4-chloro-benzenesulfonyl)-2-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. Retention time (min)=2.295, Method [1], MS (ESI) 342 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:24]([CH2:25][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:22]([OH:23])=[O:27])=[O:26]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: CNC
Product: CN(C)C(=O)Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with dimethylamine at 22° C. to give the title compound as a white solid. MS: 403.5 ([M−H]−).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (30 mg, 0.11 mmol) in DMF (2 mL) was added 1-(2-bromoethyl)-4-nitrobenzene (31 mg, 1.3 mmol) and TEA (46 uL, 0.33 mmol). The mixture was heated to 80° C. for 16 hours. LC showed some desired product at that point. The desired 1,4-bis[2-(4-nitrophenyl)ethyl]piperazine was purified by mass-directed HPLC. LC-MS (IE, m/z): 385 [M+1]+. (0.052 μM)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1CN1CCNCC1.[Li]CCCC.[CH2:39]([O:41][CH:42]=[C:43]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:40]>C1COCC1.O>[CH2:52]([O:51][C:49](=[O:50])[CH:43]([CH:42]([O:41][CH2:39][CH3:40])[CH:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH3:53]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1
Agent: [Li]CCCC
Agent: c1ccc(CN2CCNCC2)nc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)C(OCC)C(c1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 4-Pyridin-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (prepared from 1-Pyridin-2-ylmethyl-piperazine according to the literature: J. Med. Chem. (1993), 36, 2984) (2.00 g, 7.21 mmol) in THF (15 mL) was added n-BuLi (1.6 M in hexanes, 5.0 mL, 7.9 mmol) at −78° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solution was then cooled to −78° C. and a solution of diethyl ethoxymethylenemalonate (1.72 g, 7.93 mmol) in THF (2 mL) was added dropwise. The reaction mixture was allowed to warm to 0° C. over 1 hour and stirred at 0° C. for 1 hour. The reaction was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 8:1 to 1; 1) to give 2-[2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-1-ethoxy-2-pyridin-2-yl-ethyl]-malonic acid diethyl ester (2.40 g, 67%) as a mixture of diastereomers. Diastereomer 1: 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, J=4.4 Hz, 1H), 7.63 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.16 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 4.74 (m, 1H), 4.16 (m, 5H), 3.75 (q, J=7.2 Hz, 2H), 3.52 (d, J=4.4 Hz, 1H), 3.38 (m, 4H), 2.67 (m, 2H), 2.44 (m, 2H), 1.40 (s, 9H), 1.22 (m, 6H), 1.44 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.61 min. Diastereomer 2: 1H NMR (CDCl3, 400 MHz) δ 8.58 (d, J=4.8 Hz, 1H), 7.59 (td, J=7.6 Hz, J=1.6 Hz, 1H), 7.15 (dd, J=7.6 Hz, J=1.6 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.91 (m, 1H), 4.16 (m, 5H), 3.53 (m, 1H), 3.22 (m, 6H), 2.50 (m, 2H), 2.19 (m, 2H), 1.34 (s, 9H), 1.24 (m, 6H), 0.69 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 494 [M+H]+; Rt=3.62 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]12[CH:21]=[CH:20][CH:19]=[CH:18][CH:7]1[CH2:8][CH:9]2[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[I-].[K+].[N-:24]=[N+:25]=[N-:26].[Na+].OS([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O.CN(C)C=O>[N:24]([CH2:2][CH2:3][CH2:4][O:5][C:6]12[CH:21]=[CH:20][CH:19]=[CH:18][CH:7]1[CH2:8][CH:9]2[C:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])=[N+:25]=[N-:26]
Reactant: O=C(C1CC2C=CC=CC21OCCCCl)N1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCOC12C=CC=CC1CC2C(=O)N1CCCCC1
Temperature: 75 °C

Procedure:
A solution of 3-(3-chloropropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene (1.4 g), potassium iodide (4.5 g) and dimethylformamide (18.2 ml) is stirred at RT for 24 hours. Sodium azide (1.78 g) and H2O (1.82 ml) are added to the stirred mixture, which is heated for five hours at 75° C. The reaction mixture is poured into a solution of 10% NaHSO3 /NaHCO3 and extracted with methylene chloride. The organic layer is separated, washed, dried, filtered and evaporated in vacuo yielding the azide product as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.C[Si](C)(C)O[Si](C)(C)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>CN(C)P(N(C)C)(N(C)C)=O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:21]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)c1cccnc1N
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: NC(=S)c1cccnc1N
Temperature: 110 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
2-Amino-nicotinamide (1.6 g) described in Manufacturing Example 14-1, hexamethyldisiloxane (3.2 g), phosphorus pentasulfide (950 mg), and hexamethylphosphoramide (13 mL) were stirred for 18 hours at 110° C. The reaction solution was passed through a glass filter (eluted with ethyl acetate) lined with NH-silica gel and silica gel in a 1:1 ratio. The eluate was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the titled compound (290 mg).
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:11][CH:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C>[C:3]([NH:11][CH:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:13]([OH:18])[C:14]([F:15])([F:17])[F:16])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NC(Cc1ccccc1)C(O)C(F)(F)F)c1ccccc1

Procedure:
Sodium borohydride (0.37 g) is added to a solution of (3RS)-3-benzoylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane (3.12 g, Reference compound No. 30-1) in ethanol (25 ml), and the mixture is stirred at 35° C. for four hours. The reaction mixture is cooled with ice, 6 N hydrochloric acid is added to the mixture, and the whole is extracted with ethyl acetate. The extract is washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (3.00 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](OC)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: CCCCN
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Solvent: CO
Product: CCCCNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Yield: 66.8 %

Procedure:
7.05 g (0.025 mole) of 4-bromo-1-methoxy-2-nitronaphthalene is dissolved in 300 cc of methanol by heating the mixture at reflux temperature, then 5 cc (0.05 mole) of butylamine is gradually dripped into the obtained solution and when the addition is terminated the reaction mixture is still refluxed for 30 minutes with stirring. Upon cooling to 0°-5° C. a precipitate forms which is separated by filtration and dried, yielding 5.4 g of 4-bromo-N-butyl-2-nitro-1-naphthylamine. An additional 0.92 g is recovered from the mother liquor and the two crops are combined together and recrystallized from methanol. M.p. 65°-66.5° C. A mixture of 17.6 g (0.0544 mole) of this compound and 7.84 cc (0.0816 mole) of 3-chloropropionyl chloride is stirred at 60° C. for four hours. When the reaction is completed the mixture is poured in a separatory funnel and vigorously shaken with methylene chloride and a 5% aqueous NaHCO3 solution. The organic layer is separated, washed with water and dried. The residue which is obtained by evaporating off the methylene chloride is dissolved in 180 cc of EtOH and 22 cc of glacial acetic acid. 10.4 g of powdered iron is added to the obtained solution and the resulting mixture is refluxed with stirring for 20 minutes; then it is poured into 720 cc of water and extracted with methylene chloride. The methylene chloride is evaporated off, the residue is dissolved in a mixture of 125 cc of 95% EtOH and 50 cc of 10% HCl and heated at reflux temperature for 11/2 hour. The solvent is boiled off and the solid residue is triturated with ether, filtered and dried. The yield in 5-bromo-1-butyl-2-(2-chloroethyl)-1H-naphth[1,2-d]imidazole, m.p. 172° C. (dec.), is 19.4 (90.8%).
Reaction SMILES: [CH:1]12[CH2:12][CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:2]2[C:3](=[O:14])[CH:4]=[CH:5][C:6]1=[O:13].[BH4-].[Na+]>CO>[CH:8]12[CH2:11][CH2:12][CH:1]([CH:10]=[CH:9]1)[CH:2]1[CH:7]2[CH:6]([OH:13])[CH:5]=[CH:4][CH:3]1[OH:14]
Reactant: O=C1C=CC(=O)C2C3C=CC(CC3)C12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1C=CC(O)C2C3C=CC(CC3)C12
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a solution of 25.6 g of tricyclo[6.2.2.02,7]dodeca-4,9-diene-3,6-dione in 600 mL of MeOH were added 58.0 g of CeCl3 7H2O. Then, 5.7 g of NaBH4 were portionwise added at 0° C. and the mixture was stirred for 1 h at the same temperature. After evaporation of the solvent the residue was redissolved in EtOAc, it was washed with H2O, dried over MgSO4 and concentrated in vacuo. The crude was again redissolved in EtOAc and triturated with Hept to obtain 27.9 g of the desired compound as mixture of stereoisomers as brownish solid.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:34])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-])=O)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[NH4+].[Cl-].O>C1(C)C=CC=CC=1.CCOC(C)=O.[Fe]>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:19][CH2:20]1)=[O:34]
Reactant: O=C(c1ccccc1[N+](=O)[O-])N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 115 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
N-Cyclopropyl-N-[1-(2-nitro-benzoyl)-piperidin-4-yl]-3-trifluoromethyl-benzenesulfonamide (10) (0.403 mg, 0.81 mmol) was taken up in 7 ml of toluene. To the mixture, Fe (0.230 mg, 4.1 mmol), NH4Cl (0.440 g, 8.2 mmol) and H2O (0.8 ml) was added. The reaction mixture was heated at 115° C. and stirred for 3 hours. The reaction mixture was diluted with 30 ml of EtOAc, then filtrated by Celite. The filtration was concentrated and dryness under reduced pressure. The crude product was purified through a column of silica gel with a gradient of 35% to 80% EtOAc in hexane to afford the title compound 11 (pale yellow solid, 335 mg, 88%). LC: 100%. MS: m/z=467.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:25])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br.C(Cl)(Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[C:7]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([O:25][CH2:34][CH2:33][O:32][CH3:31])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:12][CH2:13]2)=[CH:6][C:5](=[O:26])[N:4]([CH3:27])[C:3]1=[O:28]
Reactant: Cn1c(N2CCN(CC(O)COc3ccc(Cl)cc3)CC2)cc(=O)n(C)c1=O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOC(COc1ccc(Cl)cc1)CN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g of 1,3-dimethyl-6-[4-(3-[4-chlorophenoxy]-2-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione was dissolved in 30 ml of dimethylformamide, and 0.25 g of sodium hydride (60% and oily) was further added thereto. The solution was stirred at room temperature for 30 minutes, and 0.85 ml of methoxyethyl bromide was then added thereto. After stirring for 3 days, 100 ml of chloroform was added to the reaction solution This solution was washed with water and then dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified through a silica gel column chromatograph (chloroform/methanol=30/1 in volume ratio), thereby obtaining 2.0 g of 1,3-dimethyl-6-[4-(3-[4-chlorophenoxy]-2-(2-methoxyethoxy)propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.