Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH2:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)=[CH:17][CH:16]=1)[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:2][CH3:3].[N:32]1[C:41]2[C:40](=O)[CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=[CH:34][CH:33]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:29]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:23][C:24]2[NH:28][CH:27]=[CH:26][N:25]=2)[CH:40]2[C:41]3[N:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH2:37][CH2:38][CH2:39]2)=[CH:19][CH:20]=1)[S:10]([CH3:13])(=[O:11])=[O:12])[CH2:30][CH3:31]
Reactant: O=C1CCCc2cccnc21
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)S(C)(=O)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)C2CCCc3cccnc32)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.7 %

Procedure:
The compound (154 mg) obtained in Example 50-2 was dissolved in anhydrous methanol (6.2 ml) and added with 6,7-dihydro-5H-quinolin-8-one (75.1 mg) which was synthesized by a known method and sodium cyanoborohydride (64.1 mg). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (69 mg) of the subject compound as a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]O)=[CH:38][CH:37]=1>>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][O:23][C:22]([C:21]2[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]3[C:19]([C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=3)=[O:24])=[CH:38][CH:37]=1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COC(=O)c2c(-c3ccccc3)c3cc(Cl)ccc3c(=O)n2N(C)C(=O)OCc2ccccc2)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 4-methoxybenzyl alcohol. A colorless powder (110 mg). HPLC analysis (Agilent 1100 system): purity 96% (retention time: 4.30 min). MS (ESI+): 583 (M+H), 585.
Reaction SMILES: C(O)C.[CH2:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.O.O.[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](=[S:20])[S-:19])[CH3:16].[Na+]>O>[CH2:15]([N:17]([CH2:21][CH3:22])[C:18](=[S:19])[S:20][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:16]
Reactant: CCN(CC)C(=S)[S-]
Reactant: ClCc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 93 %

Procedure:
More specifically, 10 ml of ethanol solution containing benzyl chloride (4.8 g, 38 mmol, Mw. 126.58) was added dropwise into 50 ml of ethanol solution containing sodium N,N-diethyldithiocarbamate trihydrate (10.3 g, 46 mmol, Mw. 225.31) in nitrogen atmosphere at 0° C. After agitating the reaction solution for 23 hours at room temperature, 150 ml of water was added and extracted by diethylether (200 ml×3 times). The organic layer was washed with water (100 ml×3 times) and was dried by sodium sulfate. Solvent was distilled away under reduced pressure using an evaporator so as to obtain benzyl N,N-diethyldithiocarbamate (colorless liquid). Yield point was 17.6 g (yield: 93%), 1H-NMR: δ7.407 ppm to 7.271 ppm (m, 5H, Ar—H), δ4.540 ppm (s, 2H, Ar—CH2S), δ4.082 ppm to 4.012 ppm (q, 2H, —N—CH2—), δ3.763 ppm to 3.692 ppm (q, 2H, —N—CH2—), δ1.311 to 1.252 ppm (m, 6H, —CH2—CH3).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=O)=[CH:12][CH:11]=1>C(O)C.C(O)(=O)C>[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][C:15]3[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[NH:7][C:16]=32)=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCc2ccc(F)cc21
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)-c1[nH]c3ccccc3c1C2
Temperature: 85 °C

Procedure:
To a solution of phenyl hydrazine (1.32 mL, 13.32 mmol) and 6-fluoro-1-indanone (2.02 g, 13.46 mmol) in ethanol (7.6 mL) was added glacial acetic acid (3 drops). The solution was stirred at reflux (85° C.) for 17 minutes and cooled to room temperature. Upon cooling, white crystals precipitated out of solution. These crystals were collected by vacuum filtration and dissolved in isopropanol (23 mL). Sulfuric acid (36N, 1.51 mL) was added via syringe and the resulting solution was stirred at reflux (90° C.) for 18 hours and subsequently cooled to room temperature. The solution was then basified to pH 10 via addition of aqueous sodium hydroxide (2% by mass) resulting in the formation of precipitate. The solid was collected by vacuum filtration to yield 37b as a brown solid in 46% crude yield (1.38 g, 6.17 mmol). Crude product was brought on to the next step without further purification. For purposes of characterization, the product was purified by flash column chromatography (20:1 to 20:1.5 hexanes-ethyl acetate). 1H NMR (600 MHz, CDCl3): δ 8.26 (s, 1H), 7.64-7.65 (d, 1H, J=7.8 Hz), 7.42-7.44 (m, 2H), 7.20-7.23 (td, 1H, J=7.2, 1.2 Hz), 7.16-7.19 (td, J=7.2, 1.2 Hz) 7.12-7.14 (dd, 1H, J=8.4, 2.4 Hz), 6.88-6.91 (m, 1H), 3.68 (s, 1H); 13C NMR (150 MHz, CDCl3): δ 161.5-163.1 (d, J=242 Hz), 142.9 (d, J=2.4 Hz), 142.3 (d, J=2.9 Hz), 140.7, 136.5 (d, J=9.6 Hz), 126.0 (d, J=9.0 Hz), 124.5, 123.9, 122.3, 120.4, 119.2, 112.2, 111.0 (d, J=22.7 Hz), 104.8 (d, J=24.3 Hz), 29.8; FTIR: cm−1 3398, 1589, 1528, 1462, 1268, 1187, 744, 665. ESI-HRMS: Calcd. for C15H10FN+ [M]+: 223.0792. found 223.0792.
Reaction SMILES: C1(COC([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23][C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=O)C=CC=CC=1>FC(F)(F)C(O)=O>[F:27][C:24]([F:25])([F:26])[S:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccccc2SC(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Sc1ccccc1C1CCNCC1
Temperature: 80 °C

Procedure:
A solution of N-phenylmethoxycarbonyl-4-[2-trifluoromethylthiophenyl]piperidine in trifluoroacetic acid was Cbz-deprotected by heating under reflux (at 80° C.) for 10 min. The mixture was concentrated to provide the product as an oil. 1H NMR (DMSO-d6) δ 7.69 (d, 1H), 7.59 (m, 1H), 7.50 (d, 1H), 7.32 (m, 1H), 3.32 (m, 2H), 3.00 (br d, 2H), 2.57 (m, 3H), 1.56 (m, 4H); MS m/z 262 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[Cl:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:17]1[CH:18]=[C:14]([Cl:13])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16]1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1n[nH]cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(Cl)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 83 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.82 g), 4-chloro-3-trifluoromethyl-1H-pyrazole (0.63 g) and potassium carbonate (0.61 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-chloro-3-trifluoromethyl-1H-pyrazole (0.98 g).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[O:12][C:11](=[O:16])[CH:10]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:32](O)(=[O:41])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N#N>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[O:12][C:11](=[O:16])[C:10]=1[C:32](=[O:41])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(O)c(C(=O)CCc2ccccc2)c(=O)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Triethylamine (1.12 ml; 8 mmol; Aldrich) was added to 4-hydroxy-6-methyl-2-pyrone (1.01 g; 8 mmol; Aldrich) in 60 ml CH2Cl2, and the reaction mixture was stirred under N2 for 10 min at 0° C. DMAP (293.3 mg; 2.4 mmol; Aldrich) and DCC (1.65 g; 8 mmol; Aldrich) were added, and the reaction mixture was stirred under N2 for 15 min at 0° C. Hydrocinnamic acid (1.20 g; 8 mmol; Aldrich) was added, and the reaction mixture was stirred N2 for 12 h at room temperature. The reaction mixture was filtered on celite to remove urea, acidified to pH ˜2 by addition of by 1 N HCl, diluted by addition of 60 ml water was added, and extracted with CH2Cl2 (2×100 ml). The organic layer was washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The product was isolated by chromatography on silica gel. Yield: 58%. MS (MALDI): calculated, m/z 259.1 (MH+); found, 259.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4]
Reactant: COc1ccc(CNC(=O)C(F)(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
Dissolve under nitrogen atmosphere 2,2,2-trifluoro-N-(4-methoxybenzyl)-acetamide (11.6 g, 50 mmol) in DCM (250 mL). Cool to 0° C. in an ice bath. Add dropwise 1M boron tribromide in DCM (100 mL, 100 mmol) and stir for 20 min after addition. Warm to ambient temperature and stir for 16 h. Cool the reaction mixture in an ice bath and quench very carefully with saturated aqueous NaHCO3. Separate the organic layer. Extract the aqueous layer twice with chloroform. Dry the combined organic extracts over-Na2SO4 and concentrate in vacuo to obtain the desired intermediate (8.8 g, 40 mmol). MS (ES−) m/z: 218 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.CC(O)C>CC(C)=O>[C:6]([O:7][CH:2]([CH3:10])[CH3:1])(=[O:8])[CH2:5][C:4]([CH3:9])=[O:3]
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(=O)CC(=O)OC(C)C
Yield: 90.2 %

Procedure:
A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (53)70 (74 g, 0.5 mol) and 2-propanol (30 g, 0.5 mol) was heated at 135° C. for 20 h. The acetone formed during the reaction was removed with a rotary evaporator. The residue was distilled to provide 65 g (0.451 mol, 90%) of 54 as a clear, colorless liquid: bp 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:18]#[C:19][CH2:20][OH:21].N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:18]#[C:19][CH2:20][O:21][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1C#CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)c1cc(OCc2ccccc2)ccc1C#CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of 5-Benzyloxy-2-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (80 g, 270 mmol) in DCM (1.5 L) was added imidazole (36.8 g, 540 mmol) and TBSCl (61 g, 405 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography column on silica gel to afford title product (90 g, 81%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.Cl.Cl.[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]([CH3:28])[CH:14]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:10][O:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:24][CH2:23]2)=[C:15]([CH3:28])[CH:14]=1
Reactant: COC(=O)c1ccc(OCCN2CCNCC2)c(C)c1
Reactant: CC(C)(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCCN2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
3,3-Dimethylbutyraldehyde (54 mg, 0.53 mmol) was added to a solution of 3-methyl-4-(2-piperazin-1-yl-ethoxy)-benzoic acid methyl ester dihydrochloride from Example E40.2 (146 mg, 0.42 mmol) in methanol/acetic acid (99:1, v/v, 10 ml) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (42 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 18 h then concentrated in vacuo. The residue was dissolved in EtOAc, washed with saturated NaHCO3, water then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (64 mg, 34%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[C:12](F)[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([F:19])[C:9]=2[F:20])[CH2:4][CH2:3]1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>C(N(CC)CC)C>[CH:21]1([NH:24][C:12]2[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([F:19])[C:9]([F:20])=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:13]=2[F:14])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: CN1CCN(c2c(F)c(F)c([N+](=O)[O-])c(F)c2F)CC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2c(F)c(F)c([N+](=O)[O-])c(NC3CC3)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
1-Methyl-4-(2,3,5,6-tetrafluoro-4-nitrophenyl)piperazine(9.4 g,34.15 mmol) is suspended in triethylamine (20 ml) and treated dropwise with cyclopropylamine (2.9 ml, 41 mmol). During the addition, the temperature is maintained below +10° C. The reaction mixture is stirred at room temperature overnight, then evaporated, suspended in ether (200 ml) and sequentially washed with 1N aqueous sodium hydroxide solution (45 ml), saturated aqueous sodium chloride solution, then dried (magnesium sulfate) and evaporated. Recrystallization from n-hexane yields 9.7 g of N-cyclopropyl-2,4,5-trifluoro-3-(4-methyl-1-piperazinyl)-6-nitroaniline as orange crystals (86%): mp:75° C.; NMR (CDCl3): 0.55 (m,2H),0.75(m,2H),2.35(s,3H),2.53(m,4H),2.92(m,1H),3.40(m,4H), 6.65(s,1H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:24]([O:26]C)=[O:25])[CH:18]=3)[NH:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:28][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]2[C:21]([CH3:23])([CH3:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:24]([OH:26])=[O:25])[CH:18]=3)[NH:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 20.2 %

Procedure:
To a stirred solution of methyl 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (149 mg, 0.37 mmol) in methanol/tetrahydrofuran (5 mL/5 mL) was added 1N sodium hydroxide (5.6 mL). The resultant mixture was heated to reflux for 2.5 h. Organic solvent was removed and the residue was dissolved in water. The aqueous layer was acidified to pH=4. The precipitates were filtered, and dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed, and after evaporation, the residue was treated with ethyl acetate to afford 29 mg of 2-(3-(N,N-dimethylsulfamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. (Yield: 20%). MS (ESI+APCI) M+1=389.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH:16][NH:17][CH:18]=O)=O)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>O1CCOCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]2[S:45][CH:18]=[N:17][N:16]=2)=[C:12]([C:20]2[CH:21]=[N:22][N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:24]=2[C:25]([F:28])([F:27])[F:26])[O:11][N:10]=1
Reactant: O=CNNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1cccc(Cl)c1-c1noc(-c2cnn(-c3cccc(Cl)c3)c2C(F)(F)F)c1-c1nncs1
Yield: 31 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (85 mg, 0.2 mmol) was treated with formic acid (6.4 μL, 0.2 mmol). The mixture was stirred at r.t. for 72 h. To the reaction mixture was added water, the resulting precipitate was collected, washed with water and dried in vacuum to give 61 mg of the intermediate as a colorless solid. To a solution of the intermediate 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(tri fluoromethyl)-1H-pyrazol-4-yl)-N′-formyl isoxazole-4-carbohydrazide (20 mg, 0.038 mmol) in dioxane (2 mL) was added Lawesson's Reagent (0.033 mL, 0.1 mmol). The mixture was stirred at reflux for 3 h. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by pTLC (EE/PE 1:1) to give 6 mg of example IB-8 as a colorless solid (yield 31%). Result of LC/MS MH+: 525.72; 1H NMR (MeOD): δ 7.35 (t, 1H), 7.49 (d, 1H), 7.59-7.71 (m, 5H), 8.37 (s, 1H), 9.38 (s, 1H)
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][NH2:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(=O)(=O)(O)O.[CH3:23]O>C(OCC)C>[C:1]([NH:11][C@H:12]([C:15]([O:17][CH3:23])=[O:16])[CH2:13][NH2:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CO
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
Dissolve Nα -(carbobenzyloxy)-β-(amino)-L-alanine (47.6 g, 0.2 mol) in methanol (500 mL) and treat with concentrated sulfuric acid (0.5 mL). Heat to 60° C. for 16 hours, cool and reduce the solvent by 50% in vacuo. Dilute with ethyl ether (500 mL), wash with saturated sodium hydrogen carbonate, then brine. Dry (MgSO4) and evaporate the solvent in vacuo to give Nα -(carbobenzyloxy)-β-(amino)-L-alanine, methyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:13])[C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[N:6][CH:7]=1.B([O-])[O-:15]>>[CH:10]1([CH2:9][O:8][C:5]2[N:6]=[CH:7][C:2]([OH:15])=[CH:3][C:4]=2[F:13])[CH2:12][CH2:11]1
Reactant: [O-]B[O-]
Reactant: Fc1cc(Br)cnc1OCC1CC1
Product: Oc1cnc(OCC2CC2)c(F)c1

Procedure:
Following Typical Procedures 4 and 5a, conversion of 5-bromo-2-cyclopropylmethoxy-3-fluoro-pyridine to the boronate and oxidation with NaBO3 provided the title compound.
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].Br[CH2:10][CH2:11][OH:12]>CO>[OH:12][CH2:11][CH2:10][S:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CCS
Reactant: OCCBr
Agent: [Na]
Solvent: CO
Product: COC(=O)CCSCCO

Procedure:
A solution of 2.3 g. sodium in 80 ml. methanol, which contains 12 g. methyl 3-mercaptopropionate and 12.5 g. 2-bromoethanol, is stirred under reflux for 4 hours. After evaporating, the residue is taken up in chloroform, filtered and evaporated. 16 g. Methyl 3-(2-hydroxyethylthio)-propionate are obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([CH3:64])[CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([CH3:64])[CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1cccc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 27 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-3-methylbenzene as starting materials in 27% yield. LCMS for C32H34ClN8O2 (M+H)+: m/z=597.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCCN1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCN1CCCC1=O

Procedure:
The 1-(2-hydroxyethyl)-2-pyrrolidinone (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[N+:12]([O-])([OH:14])=[O:13]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([C:4]1[C:5]([OH:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Temperature: 75 °C
Reaction time: 0.83 h

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone (23.7 g, 0.110 mol) in carbon tetrachloride (90 ml) was added with concentrated nitric acid (17.2 ml). The mixture was left under stirring at 75° C. for 50 minutes, then left to cool at room temperature. The precipitated solid was recovered by filtration washing with cold carbon tetrachloride. After drying under vacuum, 20.9 g of the title product were obtained as a light yellow solid (73% yield).