Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([Cl:22])[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[Cl:22][C:11]1[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=[C:15]2[C:10]=1[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2c(Cl)cc(C#N)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(C#N)cc(Cl)c3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-8-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (374.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(8-chloro-6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methylpropionic acid (118.8 mg, 30%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 398.2.
Reaction SMILES: C([O-])C.[Na+].[Cl:5][C:6]1[C:7]([O:9][C:10](=[O:13])[C:11]=1[Cl:12])=O.Cl.[CH3:15][O:16][NH2:17]>C(O)(=O)C>[Cl:12][C:11]1[C:10](=[O:13])[N:17]([O:16][CH3:15])[C:7](=[O:9])[C:6]=1[Cl:5]
Reactant: CON
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CON1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At room temperature 3.6 g (52.9 mmol) sodium ethanolate were added to a mixture of 5.6 g (33.5 mmol) 2.3-dichloro maleic anhydride and 4.6 g (55.1 mmol) methoxyamine hydrochloride in 50 ml of acetic acid. The reaction mixture was stirred 16 hours at room temperature and then poured into an ice/water mixture. An insoluble solid crystallized out which was filtered off and washed with water. Then this solid was redissolved in ethyl acetate. the solution was dried over magnesium sulfate and evaporated. 4.5 g (68% of theory) of the title compound were obtained as a light colored solid. 1H-NMR (CDCl3. δ in ppm): 4.0 (s. 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH3:13]>>[NH3:3].[CH3:12][C:4]1[N:3]=[C:2]([NH2:13])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Agent: N
Product: Cc1cc(C(F)(F)F)cc(N)n1
Temperature: 120 °C
Yield: 189.5 %

Procedure:
A mixture of 4.7 g 2-chloro-6-methyl-4-trifluoromethyl-pyridine and 80 g ammonia was heated in an autoclave at 120° C. for 24 h. Ammonia was allowed to evaporate and the residue was purified on silica gel with methylene chloride:methanol:ammonia=9:1:0.1 to yield 4.01 g of the title compound as off white crystals MS (ISP) M+H+=177.1 melting at 53.5-54.5° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH:22]=1>>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCc1cccnc1
Reactant: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Product: O=C(CCCCc1cccnc1)N1CCC(C=C(c2ccccc2)c2ccccc2)CC1
Yield: 94.2 %

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of example 10 starting with 5.27 g of 4-(2,2-diphenylethenyl)piperidine and the acid chloride prepared from 6.5 g of 3-pyridine pentanoic acid. The toluene extracts were evaporated and chromatographed on a Waters Prep 500 using silica gel columns and eluting with 98:2 ethyl acetate-triethylamine. Evaporation of the combined product fractions gave 8.0 g (94%) of crude 4-(2,2-diphenylethenyl)-1-[1-oxo-5-(3-pyridinyl)pentyl]piperidine. Crystallization of a small portion from ether gave analytically pure 4-(2,2-diphenylethenyl)-1-[1-oxo-5-(3-pyridinyl)pentyl]piperidine, mp 82°-84° C. Analysis Calculated for C29H32N2O: C, 82.04; H, 7.60; N, 6.60. Found: C, 81.88; H, 7.63; N, 6.67.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12](COCC[Si](C)(C)C)[C:11]3[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=3[N:9]=2)[CH:4]=1.Cl>CO>[CH3:1][S:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[NH:9][C:10]3[CH:24]=[CH:23][CH:22]=[CH:21][C:11]=3[N:12]=2)[CH:4]=1
Reactant: CSc1cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)no1
Agent: Cl
Solvent: CO
Product: CSc1cc(-c2nc3ccccc3[nH]2)no1
Yield: 93.8 %

Procedure:
A mixture of 2-(5-methylsulfanyl-isoxazol-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (160 mg, Reference Example 12), methanol (12 mL) and concentrated aqueous hydrochloric acid (2.45 mL) were heated at reflux for four hours, then cooled and then evaporated. The residue was treated with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extracts were dried and then evaporated to give 2-(5-methylsulfanyl-isoxazol-3-yl)-1H-benzoimidazole (96 mg) as an off white solid, mp 179-181° C. 1H-NMR [(CD3)2SO]: δ 4.65 (s, 3H), 9.00 (s, 1H), 9.15-9.6 (m, 4H).
Reaction SMILES: NC(N)=[O:3].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])(=[O:29])=[O:28])=[CH:23][N:22]=1.O>ClCCl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])(=[O:29])=[O:28])=[CH:23][N+:22]=1[O-:3]
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccccc1F
Reactant: NC(N)=O
Agent: OO
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)[n+]([O-])c1)c1ccccc1F
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Urea-hydrogen peroxide (0.36 g, 3.83 mmol) was suspended in dichloromethane (3 mL) and trifluoroacetic anhydride (0.77 g, 3.67 mmol) was added to form a clear solution. 2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1 Steps 1 and 2, 0.5 g, 1.84 mmol) in dichloromethane (1 mL) was added and the reaction stirred at room temperature under nitrogen for 7 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium thiosulfate (×3). The combined aqueous layers were extracted once with ethyl acetate, then the combined organic layers washed again with sodium thiosulfate then with brine, dried over MgSO4 and concentrated in vacuo to give 2-chloro-5-[(2-fluorophenyl)sulfonyl]pyridine 1-oxide as a pale yellow solid (0.53 g, quant.). δH (500 MHz, d6 DMSO): 8.84 (1H, d, J=1.5 Hz), 8.08 (1H, td, J=7.5, 1.5 Hz), 8.03 (1H, d, J=8.6 Hz), 7.87-7.77 (2H, m), 7.51 (1H, q, J=8 Hz), 7.47 (1H, d, J=8.6 Hz); m/z (ES+) 288[MH+].
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[N:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[N:21][C:22]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])=[C:17]([O:16][CH3:15])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: COc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 61 %

Procedure:
The title compound is prepared in 61% yield (140 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (163 mg, 0.57 mmol, Amine-9, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
Using 3-(1-cyanocyclopropyl)-N-(3-hydroxy-4-methylphenyl)benzamide (1.46 g, 5.0 mmol), 1-fluoro-4-nitrobenzene (0.77 g, 5.5 mmol) and potassium carbonate (0.69 g, 5.0 mmol), and in the same manner as in Example A25(iii), the title compound (2.07 g, quantitatively) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1>N1CCCCC1>[N:4]1([C:2]2[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=2)[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]1
Reactant: [O-][n+]1cccc(Cl)c1
Solvent: C1CCNCC1
Product: [O-][n+]1cccc(N2CCCCC2)c1
Yield: 133.4 %

Procedure:
A solution of 3-chloro-pyridine 1-oxide (2.40 g, 18.5 mmol) in piperidine (6 mL) was heated at 140° C. for 2 days. After the reaction mixture was cooled to room temperature the amine was removed, and the residue was purified by flash chromatography on a silica gel column (6:1 EtOAc/MeOH), affording 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl 1′-oxide as a pale yellow solid (2.20 g, 67%). 1H NMR (CDCl3) δ 1.59-1.67 (m, 6H), 3.14-3.18 (m, 4H), 6.78 (dd, 1H, J=2.1, 8.7 Hz), 7.03 (dd, 1H, J=6.3, 8.7 Hz), 7.63-7.66 (m, 1H), 7.85-7.86 (m, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:10]1[C:11]2[C:16]([C:17]3[CH:18]=[C:19]4[O:26][CH2:25][O:24][C:20]4=[CH:21][C:22]=3[CH:23]=1)=[CH:15][C:14]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:13][CH:12]=2.N>>[CH2:25]1[O:26][C:19]2[C:20](=[CH:21][C:22]3[CH:23]=[C:10]([CH2:9][N:5]4[CH2:6][CH2:7][CH2:8][C@H:4]4[CH2:3][OH:2])[C:11]4[C:16]([C:17]=3[CH:18]=2)=[CH:15][C:14]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:13][CH:12]=4)[O:24]1
Reactant: COC(=O)[C@@H]1CCCN1Cc1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3
Agent: N
Product: OC[C@@H]1CCCN1Cc1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3

Procedure:
General procedure f from 17 (95%); colorless oil, recrystallization from EtOH gave white powder; mp 122-124° C.; 1H NMR (400.13 MHz) δ 8.13 (d, J=4 Hz, 1H), 7.90 (d, J=2 Hz, 1H), 7.84 (s, 1H), 7.51 (d, J=4 Hz, 2H), 7.42 (s, 1H), 7.41 (t, J=4 Hz, 2H), 7.34 (m, 1H), 7.29 (dd, J=4 Hz, 2 Hz, 1H), 7.14 (s, 1H), 6.06 (s, 2H), 5.24 (s, 2H), 4.36 (d, J=7 Hz, 2H), 3.78 (d, J=17 Hz, 2H), 3.41 (m, 1H), 2.42 (m, 2H), 1.83 (m, 2H), 1.66 (m, 6H); MS (DCI/NH3) m/e: 442 (M+H)+. Anal. (C28H27O4N) C, H, N.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15][CH:14]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:13]1=[O:37])=[O:10])C1C=CC=CC=1>CO.[C].[Pd]>[O:37]=[C:13]1[N:12]([CH2:11][C:9]([OH:10])=[O:8])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]([C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:15][CH:14]1[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)O)C1=O
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
10% Palladium carbon (300 mg) was added to a suspension of 1-benzyloxycarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (3.0 g) in methanol (100 ml), the mixture was stirred for 30 minutes under hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the residue for trituration and filtrated, to thereby obtain 2.46 g of the title compound (Yield: 99.6%) as pale yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]([CH3:33])[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:33][N:19]1[C:18]([CH2:17][CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=2)=[CH:22][C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][CH:24]=2)=[N:20]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 1 f], (6-{2-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain (6-{2-[2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-ethoxy}-indol-1-yl)-acetic acid as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:25]([C:27]([CH2:32][CH3:33])([CH2:30]O)[CH2:28]O)[CH3:26]>O1CCCC1>[CH2:16]([O:15][C:13]([C:8]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:10]2[C:9]=1[O:12][CH2:30][C:27]([CH2:32][CH3:33])([CH2:25][CH3:26])[CH2:28][O:11]2)=[O:14])[CH3:17]
Reactant: CCC(CC)(CO)CO
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(c(C(=O)OCC)n1Cc1ccccc1)OCC(CC)(CC)CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
ADC01 (2.9 g, 16.9 mmol) was slowly added to a solution of N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylic acid diethyl ester (2.6 g, 7.7 mmol), 2,2-diethyl-1,3-propanediol (1.1 g, 8.5 mmol), and PH02 (4.4 g, 16.9 mmol) in dry tetrahydrofuran (150 ml) at 0° C. The reaction mixture was then allowed to warm to 25° C., stirred for 3 h, and then was refluxed for 21 h. The reaction mixture was then allowed to cool to 25° C. and was concentrated by rotary evaporator to remove the tetrahydrofuran. The residue was then diluted with diethyl ether and allowed to stand overnight to enable the tributylphosphine oxide to precipitate out. The tributylphosphine oxide was then removed by filtration and the remaining product was purified by chromatography on silica gel (eluant: ethyl acetate/hexane=3/1) to give 2-benzyl-6,6-diethyl-6, 7-dihydro-2H,5H-4,8-dioxa-2-aza-azulene-1,3-dicarboxylic acid diethyl ester as a colourless oil in 2.5 g (75%) yield as characterized by 1H NMR, 13C NMR, HRMS, and elemental analysis.
Reaction SMILES: [C:1]12[C:12]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:1]12[C:12]([O:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2cccc3sc4c(c23)CCC4)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: NC1CCC(Oc2cccc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Into a 50-mL round-bottom flask placed tert-butyl N-(4-[7-thiatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexyl)carbamate (200 mg, 0.52 mmol, 1.00 equiv) in 16 mL of dichloromethane was added hydrochloric acid (0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature. Then the pH value was adjusted to 8-9 with saturated aqueous sodium carbonate and extracted with 3×50 mL of ethyl acetate and the organic layers combined. The organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the resulted 4-[7-thiatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yloxy]cyclohexan-1-amine (140 mg, 90% purity) as a white solid which was used for next step without further purification. MS (ES, m/z): 290 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.CO[C:18](=[O:38])[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([O:30][CH2:31]C2C=CC=CC=2)[CH:22]=1)[CH3:20]>>[NH:14]([C:31]1[O:30][C:23]2[CH:22]=[C:21]([CH:19]([C:18]([NH:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:15])[CH:13]=3)=[O:38])[CH3:20])[CH:26]=[CH:25][C:24]=2[N:27]=1)[C:12]1[CH:13]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: COC(=O)CCCOc1cccc(N)c1
Product: CC(C(=O)Nc1cccc(OCCCC(=O)O)c1)c1ccc2nc(Nc3ccccc3)oc2c1

Procedure:
Methyl4-(5-aminophenoxy)butyrate was made as described in example 7 above and coupled with methyl-2-(3-benzyloxy-4-nitrophenyl)propionate according to the method described in example 7 to produce the methyl ester of 2-anilino-6-(1-(3-[3-carboxypropoxy]anilino carbonyl)ethyl)benzoxazole.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[F:14][C:15]([F:23])([F:22])[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1>C1COCC1>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([N:18]2[CH2:19][CH2:20][CH2:21][CH:16]([C:15]([F:23])([F:22])[F:14])[CH2:17]2)[C:3]=1[C:4]#[N:5]
Reactant: FC(F)(F)C1CCCNC1
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1N
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-amino-6-fluoro-3-nitrobenzonitrile (3.1 g, 17 mmol), 3-trifluoromethylpiperidine (2.5 g, 19 mmol), TEA (3.4 g, 34 mmol) and THF (110 mL) was stirred under Ar at rt for 3 h. The mixture was concentrated and poured into H2O and thereafter extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc gave the sub-title compound.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Cl-].C([Al+2])C.[CH:16]([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:17]>ClCCCl.CCCCCC>[C:19]1([S:18][CH:16]2[CH2:17][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]2[C:1]([O:9][CH3:10])=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)/C=C/C(=O)OC
Reactant: C=CSc1ccccc1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCCCCC
Product: COC(=O)C1CC(Sc2ccccc2)C1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 1.06 g (7.34 mmol) of dimethyl fumarate in 20 mL of dry 1,2-dichloroethane under nitrogen atmosphere, was added with stirring, 7.34 mmol of a 1.0 M solution of ethylaluminum dichloride in hexane. The resultant yellow solution was heated to reflux and a solution of 1.0 g (7.34 mmol) of phenyl vinyl sulfide in 4 mL of dry 1,2-dichloroethane was added dropwise, via syringe, over a period of 20 minutes. The reaction mixture was allowed to stir at reflux for 3 h. After cooling to ambient temperature, the reaction was quenched carefully with 100 mL of 1.0 N hydrochloric acid solution and the reaction mixture was extracted with 3×50 mL of ethyl acetate. The organic extract was washed with 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a viscous orange oil. The oil (1.56 g) was chromatographed on silica gel (25 g) eluted with 300 mL of 3% ethyl acetate in 1,2-dichloroethane. The resultant yellow oil was purified by bulb-to-bulb distillation to give the title compound as a yellow oil; b.p 120° C. (0.05 mm Hg); EI-MS, m/e (relative intensity): 280 (M+, 18), 136 (100), 91 (13); 1H NMR (CDCl3) δ2.20 (q, 1H), 2.61 (m, 1H), 3.22 (q, 1H), 3.34 (t, 1H), 3.66 (s, 3H), 3.67 (s, 3H), 3.87 (m, 1H), 7.30 (m, 5H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[CH3:65])[CH3:50]>CN(C=O)C>[CH2:49]([O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)=[CH:54][C:53]=1[CH3:65])[CH3:50]
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1C
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.5 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.067 mmol) and HATU (0.028 g, 0.072 mmol) in 0.37 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.067 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.011 g of product in 41% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:19])[C:11]3[N:12]([N:14]=[C:15]([CH2:17]O)[CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:21]>ClCCl>[Br:21][CH2:17][C:15]1[CH:16]=[C:11]2[C:10](=[O:19])[NH:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:13][N:12]2[N:14]=1
Reactant: BrP(Br)Br
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cn2nc(CO)cc12
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccc(Br)cc2)cn2nc(CBr)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 142 mg (0.445 mmol) 6-(4-bromo-phenyl)-2-hydroxymethyl-5H-pyrazolo[1,5-a]pyrazin-4-one in 8 ml dichloromethane is added 52 μl (0.56 mmol) phosphorus tribromide. The reaction mixture is stirred for 20 hours at room temperature. The mixture is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate and evaporated. Purification by preparative HPLC (RP18 silica gel, eluent water/acetonitrile/formic acid) affords 2-bromomethyl-6-(4-bromo-phenyl)-5H-pyrazolo[1,5-a]pyrazin-4-one as off-white solid; HPLC/MS 2.21 min (A), [M+H] 384.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH:3]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:9]([CH3:10])[CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(C)C(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: COC(OC)OC
Product: CC(C)C1(c2cccc(Br)c2)OCCO1
Temperature: 60 °C
Reaction time: 48 h
Yield: 81.5 %

Procedure:
150 mg of 1-bromo-3-isobutyrylbenzene, 204 mg of ethylene glycol, 350 mg of trimethylorthoformate, and 10 mg of p-toluene sulfonic acid were dissolved in 4 mL of toluene, followed by stirring at 60° C. for 2 days. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 146 mg (yield 80%) of a title compound as a pale yellow oily substance.