Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@@H:15]([C:17]([NH:19][CH2:20][C:21]([OH:23])=O)=[O:18])[CH3:16])=[O:13])=[O:9])[CH3:7])=[O:4].Cl.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[NH:1]1[C:21](=[O:23])[CH2:20][NH:19][C:17](=[O:18])[C@@H:15]([CH3:16])[NH:14][C:12](=[O:13])[CH2:11][NH:10][C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[CH2:2]1
Reactant: C[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1NC(=O)CNC(=O)CNC(=O)[C@@H](C)NC(=O)CNC1=O
Temperature: -40 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
This compound was synthesized by the method of Veber, D. F. et al, J. Org. Chem. 44, 3101-5 (1979). To a solution of Gly-Ala-Gly-DAla-Gly.circle-solid.HCl prepared as in Example 34D (9.70 g, 26.4 mmol) in anhydrous DMF (3200 ml) was added enough TEA to adjust the pH to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the resulting mixture was cooled to -40° C. To this mixture was added DPPA (8.86 g, 32.2 mmol) dropwise over 5 min. The temperature was maintained at ~-35 ° C. for a period of 5 h and then the reaction mixture was stored at -25° C. (internal temperature) for 48 h thereafter. During this time the pH was monitored periodically (as described above) and maintained at ~8 by the addition of TEA. After this time the reaction mixture was allowed to stand at 0° C. for 48 h. Again the pH was monitored periodically and maintained at ~8 by the addition of TEA. After this time the reaction was diluted with water (3200ml) and stirred with Bio-Rad AG 501-X8 (mixed-bed) resin (1500 g) for 6 h. The resin was separated by filtration and the solution was concentrated to dryness. Trituration of the residue with refluxing THF for 12 h, filtration of the hot THF and drying at high vacuum afforded 5.50 g (67 % yield) of the product as a white powder: mp >300° C. (dec); 1H NMR (DMSO-d6) δ 1.16-1.25 (m, 6H), 3.38-4.23 (m, 8H), 7.55 (t, J=5.6 Hz, 1H), 7.60 (t, J=5.4 Hz, 1H), 8.20-8.25 (m, 1H), 8.40 (d, J=7.6 Hz, 1H); FAB mass spectrum (NBA+Li+) m/z 320 (M+Li)+.
Reaction SMILES: I[CH2:2][CH2:3][CH3:4].[CH:5]1([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH:5]1([NH:8][C:9](=[O:35])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([N:28]5[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH3:4])[CH2:30][CH2:29]5)[CH:24]=4)[N:19]=[CH:18]3)[CH:11]=2)[CH2:7][CH2:6]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCCNCC3)cc2c1=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN1CCCN(c2ccc3ncn(-c4cc(C(=O)NC5CC5)ccc4C)c(=O)c3c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Iodopropane (0.039 ml) was added to a stirred mixture of N-cyclopropyl-3-[6-(1,4-diazepan-1-yl)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzamide (0.150 g) and potassium carbonate (0.199 g) in DMA (0.50 ml). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (20 ml), the resulting solid was filtered and dried (magnesium sulphate) under vacuum at 40° C. There was thus obtained the title compound (0.098 g); NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.68 (m, 2H), 0.80 (t, 3H), 1.39 (m, 2H), 1.87 (m, 2H), 2.11 (s, 3H), 2.36 (t, 2H), 2.49 (m, 2H), 2.72 (m, 2H), 2.84 (m, 1H), 3.56 (m, 4H), 7.23 (d, 1H), 7.36 (d, 1H), 7.50 (d, 1H), 7.58 (d, 1H), 7.79 (s, 1H), 7.87 (d, 1H), 7.95 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.O.[NH2:10][NH2:11]>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:10][NH2:11])=[CH:6][CH:7]=1
Reactant: NN
Reactant: Clc1ccc(Cl)nn1
Solvent: O
Solvent: C1CCOC1
Product: NNc1ccc(Cl)nn1

Procedure:
A solution of 3,6-dichloropyridazine (3 g, 20.14 mmol) and hydrazine monohydrate (1 g, 20.14 mmol) in 20 mL THF in a sealed tube was heated at 80° C. for 5 h. Solvent was evaporated and the crude was used in the next step without purification (3.56 g, 100%). LCMS (method B): [MH]+=145.1, tR=0.574 min.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[CH:11][NH:12][C:13]1[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:20])[C:14]2[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]=2[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(c1=O)C(=O)CCC2
Yield: 722.7 %

Procedure:
A mixture of 2-[(3-oxo-cyclohex-1-enylamino)-methylene]-malonic acid diethyl ester (2.8 g, 1 mmol) and diphenylether (20 mL) was refluxed for 15 min. After cooling, n-hexane (80 mL) was added. The resulting solid was isolated via filtration and recrystallized from methanol to give 4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester (1.7 g 72%).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([OH:20])[C:17]#[C:18][CH3:19].[CH3:21][CH:22]1[CH2:27][CH:26]([CH3:28])[CH2:25][NH:24][CH2:23]1>O.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:16]([O:20][C:2]1[C:7]([F:8])=[C:6]([N:24]2[CH2:25][CH:26]([CH3:28])[CH2:27][CH:22]([CH3:21])[CH2:23]2)[N:5]=[CH:4][N:3]=1)[C:17]#[C:18][CH3:19]
Reactant: CC1CNCC(C)C1
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1F
Temperature: 30 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture obtained by adding 110.0 g of 4,5,6-trifluoropyrimidine, 114.6 g of potassium carbonate and 16.6 g of triethylamine to 220.0 g of toluene, 60.4 g of 2-butyn-1-ol was added dropwise at 25 to 30° C. over one hour, followed by stirring at 30° C. for 8 hours. Then, 220.0 g of water was added dropwise in the reaction mixture, followed by stirring for 14 hours. Then, 97.5 g of 3,5-dimethylpiperidine (a mixture of a cis-isomer and a trans-isomer in a mixing ratio of about 7:3) was added dropwise and, after the mixture was stirred at 30° C. for 6 hours, the reaction mixture was allowed to stand. After separating into the organic layer and the aqueous layer, the aqueous layer was removed and the organic layer was then washed once with 220.0 g of 5% hydrochloric acid and then washed once with 220.0 g of water. The organic layer was concentrated to obtain 213.8 g (yield: 94%) of 4-(2-butynyloxy)-5-fluoro-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter referred to as the present compound (3)). Product purity 96% (HPLC)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[C:37]([I:46])[CH:36]=1.[CH2:47]=[C:48]([CH2:51][CH2:52][OH:53])[CH2:49]O>O1CCCC1>[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([N:39]([CH2:49][C:48](=[CH2:47])[CH2:51][CH2:52][OH:53])[S:40]([CH3:43])(=[O:42])=[O:41])=[C:37]([I:46])[CH:36]=1
Reactant: C=C(CO)CCO
Reactant: CS(=O)(=O)Nc1ccc(Cl)cc1I
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(CCO)CN(c1ccc(Cl)cc1I)S(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a stirred solution of triphenylphosphine (2.75 g) in tetrahydrofuran (60 ml) at −10° C. under argon was added dropwise diisopropylazodicarboxylate (DIAD, 2.1 ml); the resulting suspension was stirred at −10° C. for 15 min then 4-chloro-2-iodo-N-methanesulfonyl-aniline (3.1 g) was added as a solid followed by 2-methylene-butane-1,4-diol (0.95 g) dissolved in a minimum of tetrahydrofuran. The reaction mixture was stirred at room temperature for 6 hours, the solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (eluent ethyl acetate:cyclohexane 4:6) to afford N-(4-Chloro-2-iodo-phenyl)-N-(4-hydroxy-2-methylene-butyl)-methanesulfonamide (3.5 g) contaminated with triphenylphosphine oxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:43](=[O:44])[NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2C(=O)Nc1ccccc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 8 h

Procedure:
990 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 10 ml dichloromethane. 598 mg potassium carbonate and 247 μl phenylisocyanate are added. After stirring overnight the solid is filtered off and washed twice with dichloromethane. The combined organic phases are evaporated down in vacuo and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 10:1 to 1:2).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:12]([C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)#[C:13][CH3:14].O>C(NCC)C.[Cu](I)I>[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([C:1]#[C:2][CH3:3])=[CH:9][CH:8]=2)=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: CC#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CCC)cc1
Agent: I[Cu]I
Solvent: O
Solvent: CCNCC
Product: CC#Cc1ccc(C#Cc2ccc(CCC)cc2)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
4-Propylphenylacetylene (7.21 g, 0.05 mol) and 4-(1-propynyl)iodobenzene (12.1 g, 0.05 mol) were dissolved in diethylamine (30 cc), and then copper iodide (0.29 g, 1.5 mmol) and dichlorobistriphenylphosphinepalladium dichloride (0.53 g, 0.75 mmol) were added. The resulted mixture was reacted with stirring in nitrogen gas current at about 20° C. for 8 hours. After completion of the reaction, water (100 ml) was added to the resulting reaction mixture. The resulting deposited mass was extracted with toluene (50 ml). The resulting toluene solution was washed with dilute hydrochloric acid, followed by water until the washing water became neutral. The resulting material was dried over anhydrous sodium sulfate. Toluene was distilled off from the toluene solution. The residue was then dissolved in a mixed solvent of n-hexane/methylene chloride (1 vol./1 vol.). The solution was subjected to column chromatography using silica gel as a fixed phase, and using the above mixed solvent as an eluent. Fractions showing a single spot were collected by TLC and the mixed solvent was distilled. The residue after distillation was recrystallized from ethyl alcohol (20 ml) to obtain the objective 4-propyl-4'-(1-propynyl)tolan (compound No. 1) (6.7 g). This compound exhibited liquid crystal phases (CI point: 87.7° C., NI point: 85.1° C.).
Reaction SMILES: Cl.Cl.Cl.NCC1CN(CC#CC2C=NC=CC=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](NC(=O)CC3C=CC(F)=CC=3)=[O:28])=[CH:22][C:21]=2[F:40])C1.[Cl:41][C:42]1[CH:47]=[C:46]([N+]([O-])=O)[CH:45]=[CH:44][N:43]=1.[C:51]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:41][C:42]1[CH:47]=[C:46]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[CH3:51])=[CH:22][C:21]=2[F:40])[CH:45]=[CH:44][N:43]=1
Reactant: O=C([O-])[O-]
Reactant: NCC1CN(CC#Cc2cnccc2Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)C1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Temperature: 100 °C
Yield: 72.4 %

Procedure:
A mixture of N-(3-fluoro-4-hydroxyphenyl)acetamide (Compound A of Example 13, 1.33 g, 7.87 mmol), 2-chloro-4-nitropyridine (Aldrich, 1.24 g, 7.87 mmol), K2CO3 (1.6 g, 11.8 mmol), and DMF (25 mL) was heated at 100° C. for 9 h. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 eluting with 30-80% EtOAc in hexanes to give the title compound (1.6 g, 73%) as a pale yellow solid. 1H NMR (DMSO-d6) δ 10.25 (s, 1H), 8.35 (d, 1H, J=7 Hz), 7.80 (d, 1H, J=14 Hz), 7.50 (d, 1H, J=3 Hz), 7.33 (m, 2H), 7.02 (m, 1H), 2.06 (s, 3H); MS(ESI+): m/z 281.16 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=2)=[C:8]([CH2:19][CH3:20])[C:7](=[O:21])[NH:6][C:5]1=[O:22])[CH:2]=[CH2:3].ClC1C(C(OO)=[O:31])=CC=CC=1>ClCCl>[O:31]1[CH2:3][CH:2]1[CH2:1][N:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:8]([CH2:19][CH3:20])[C:7](=[O:21])[NH:6][C:5]1=[O:22]
Reactant: C=CCn1c(Oc2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reactant: O=C(OO)c1ccccc1Cl
Solvent: ClCCl
Product: CCc1c(Oc2cc(C)cc(C)c2)n(CC2CO2)c(=O)[nH]c1=O
Yield: 34.6 %

Procedure:
1-Allyl-5-ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione 157 mg, 0.52 mmol) was dissolved in dichloromethane (10 ml), and thereto chloro perbenzoic acid (385 mg, 1.56 mmol) was added. The resulting solution was refluxed for 24 hours, washed with a saturated solution of sodium bicarbonate, distilled under the reduced pressure to remove the used solvent and purified with column chromatography to obtain the titled compound as white solid (57 mg, yield: 35.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]([NH2:19])=[NH:18])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[C:25]([O-:28])([O-])=[O:26].[Cs+].[Cs+].[OH:31]/[CH:32]=[C:33](/[CH2:38][C:39]1[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=1)\[C:34](OC)=O>CN1C(=O)CCC1>[F:22][C:21]([F:24])([F:23])[C:25]([OH:28])=[O:26].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:20])[C:17]3[NH:19][CH:34]=[C:33]([CH2:38][C:39]4[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=4)[C:32](=[O:31])[N:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C([O-])[O-]
Reactant: CN(Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)C(=N)N
Reactant: COC(=O)/C(=C\O)Cc1cnn(C)c1
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN(Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cnn(C)c2)c[nH]1
Product: O=C(O)C(F)(F)F
Temperature: 130 °C
Yield: 30.1 %

Procedure:
To the mixture of N-[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]-N-methylguanidine (50 mg, 0.140 mmol) and Cs2CO3 (182 mg, 0.559 mmol) in NMP (1 mL), was added methyl (2Z)-3-hydroxy-2-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-propenoate (40 mg, 0.204 mmol). It was heated with a microwave reactor at 130° C. for 1 h. Purification via MDAP then afforded the title compound as a white solid (13 mg, 15.1% yield). LCMS: rt=3.03 min, [M+H+]=504
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:12].C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.[NH2:26][C:27]([CH3:34])([CH2:32][CH3:33])[C:28](=[O:31])[CH2:29][Cl:30]>O1CCCC1>[NH2:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([C:6]([NH:26][C:27]([CH2:32][CH3:33])([CH3:34])[C:28](=[O:31])[CH2:29][Cl:30])=[O:8])=[CH:9][C:10]=1[Cl:11]
Reactant: CCC(C)(N)C(=O)CCl
Reactant: Nc1c(Cl)cc(C(=O)O)cc1Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(NC(=O)c1cc(Cl)c(N)c(Cl)c1)C(=O)CCl
Temperature: 25 °C
Yield: 82.9 %

Procedure:
In a 100 mL three-necked round-bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer was placed 0.62 g (3 mmol) of 4-amino-3,5-dichlorobenzoic acid, 20 mL of tetrahydrofuran, and 1.52 g (15 mmol) of triethylamine. To the resulting well-stirred mixture was added 0.4 g (3.3 mmol) of methanesulfonyl chloride dropwise while keeping the reaction temperature at -25° C. The resulting suspension was stirred at -25° C. for 30 minutes, after which 0.7 g (3.8 mmol) of 3-amino-1-chloro-3-methyl-2-pentanone hydrochloride was added slowly over a 45 minute period. After the addition was complete, the reaction mixture was stirred at -25° C. for an additional 60 minutes. The cooling bath was removed; the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was poured into a mixture of water and ethyl acetate. The phases were separated and the aqueous layer was extracted several times with ethyl acetate. The combined organic phases were washed sequentially with water, saturated aqueous sodium bicarbonate, and water, then dried over anhydrous magnesium sulfate. The resulting solution was treated with charcoal and filtered through Celite™. The solvent was removed using a rotary evaporator, yielding 0.84 g of 4-amino-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide as a white solid, mp 134-138° C.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[N:6]2[CH2:23][C:24]([F:27])([F:26])[F:25]
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CC(F)(F)F)c2ccc([N+](=O)[O-])c(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 1610.7 %

Procedure:
A suspension of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (0.10 g), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.16 g), potassium carbonate (0.12 g) and DMF (2 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.2 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][O:21]2)[C:10]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[O:11])=[CH:5][C:4]=1[C:25]([F:28])([F:27])[F:26].C(O)=[O:30].OO.[Mn]([O-])(=O)(=O)=O.[K+].[OH2:40]>CO>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:19][C@H:20]2[CH2:24][CH2:23][CH2:22][O:21]2)[C:10]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[O:11])=[CH:5][C:4]=1[C:25]([F:28])([F:26])[F:27])(=[O:30])=[O:40]
Reactant: CSc1ccc(C(C[C@H]2CCCO2)C(=O)Nc2cnccn2)cc1C(F)(F)F
Reactant: O=CO
Reactant: O
Agent: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCCO2)C(=O)Nc2cnccn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
A solution of 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-furan-2(R)-yl)-propionamide (0.054 g, 0.13 mmol) in formic acid (0.16 mL, 3.0 mmol) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (0.08 mL, 0.65 mmol). The resulting solution was stirred at 0° C. for 30 min and was then quenched with a 10% aqueous sodium bisulfite solution. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in methanol (1 mL) and was treated dropwise with a solution of potassium permanganate (0.023 g, 0.143 mmol) in water (0.5 mL). The dark brown solution was stirred at 25° C. for 30 min and then was diluted with methanol (10 mL). The reaction mixture was filtered to remove solids, and the filtrate was concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 7/3 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-furan-2(R)-yl)-propionamide (33 mg, 57.3%) as a colorless gum: EI-HRMS m/e calcd for C19H20F3N3O4S (M)+ 443.1127. found 443.1137.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[CH:10]=1)([O-:5])=[O:4].[CH2:20](O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC.O>[CH3:18][C:17]1([C:15]2[O:16][C:12]([CH2:11][N:9]3[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[N:8]3)=[CH:13][CH:14]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: CC(=O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(Cn3cc([N+](=O)[O-])cn3)o2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-[5-(4-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-ethanone (3.40 g, 14.46 mmol), ethylene glycol (8.1 mL, 144.84 mmol) and TsOH (28 mg, 0.15 mmol) in toluene (150.0 mL) was heated to reflux for 4 h. The reaction mixture was allowed to cool to rt. Water (200 mL) and EA (40 mL) were added and the aq. phase was extracted with EA (2×80 mL). The combined org. extracts were washed with sat. aq. NaHCO3 (200 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a yellow oil. TLC: rf (60:40 hept-EA)=0.31. LC-MS-conditions 02: tR=0.91 min. 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 3H), 3.99 (dd, J=4.5, 2.5 Hz, 2H), 4.06 (dd, J=4.4, 2.5 Hz, 2H), 5.31 (s, 2H), 6.35 (d, J=3.3 Hz, 1H), 6.42 (d, J=3.3 Hz, 1H), 8.09 (s, 1H), 8.12 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][C:7]=3[CH:8]=2)[NH:3]1.[H-].[Na+].CI.[C:26](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:26][N:3]1[C:4]2[C:9](=[CH:8][C:7]3[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16][C:6]=3[CH:5]=2)[CH2:10][CH2:11][C:2]1=[O:1]
Reactant: O=C([O-])O
Reactant: CCOC(=O)N1CCc2cc3c(cc2CC1)NC(=O)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)N1CCc2cc3c(cc2CC1)N(C)C(=O)CC3
Reaction time: 1 h

Procedure:
287 mg of ethyl 2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate was dissolved in 5 ml of DMF, and 65 mg of 60% sodium hydride was added thereto in an ice-bath, followed by stirring for 1 hour. 0.3 ml of methyl iodide was added thereto, followed by stirring at room temperature for 3 hours. Then, a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The solvent was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 94 mg of ethyl 1-methyl-2-oxo-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a colorless solid.