Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: IC1CCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(C4CCCC4)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH2:17][C:16](=O)[CH2:15]1>[Pd]>[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH2:17][CH:16]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:7][CH:8]=2)[CH2:15]1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CC(C)(C)Oc1ccc(N)cn1
Agent: [Pd]
Product: CN1CC(Nc2ccc(OC(C)(C)C)nc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-tert.butoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:24])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:32](Br)([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[O:24][C:19]=2[CH:18]=1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (Z)-6-bromo-4-((3,4-dihydroxybenzylamino)methylene)isoquinoline-1,3(2H,4H)-dione (195 mg, 0.50 mmole), dimethylformamide (5 mL), potassium carbonate (415 mg, 3.0 mmole) and diethyl 2,2-dibromomalonate (159 mg, 0.50 mmole) is stirred at room temperature overnight. The reaction mixture is filtered and washed with dimethylformamide, the filtrate is evaporated dissolved in 2% methanol in chloroform and passed through a pad of Florisil. The eluate is evaporated to give a beige solid, 114 mg, (41%), mp 222-3° C.; MS (ES+): m/z 545.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[C:22]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[CH:16]=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:20][CH2:21][C:22]4[O:14][CH:15]=[CH:16][C:17]=4[CH2:18]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2occc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[C:8]([OH:10])=[O:9])=[O:5].[OH-].[Na+:34]>C1COCC1>[Na+:34].[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([C:20]2([O:26][CH3:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[C:8]([O-:10])=[O:9])=[O:5]
Reactant: COC1(c2ccc(/C=C/C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC1(c2ccc(/C=C/C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)[O-])cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid (4.24 g), THF (8.86 ml) and 1N aqueous sodium hydroxide solution (8.86 ml) were added, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction solution was concentrated to dryness to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid sodium salt (4.30 g).
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:16]=[CH:15][C:10]2[S:11][CH:12]=[C:13]([CH3:14])[C:9]=2[CH:8]=1.[Cl:17][CH2:18][CH2:19][CH2:20]I.[NH4+].[Cl-]>C1COCC1.[Cu]I>[Cl:17][CH2:18][CH2:19][CH2:20][C:12]1[S:11][C:10]2[CH:15]=[CH:16][C:7]([F:6])=[CH:8][C:9]=2[C:13]=1[CH3:14]
Reactant: ClCCCI
Reactant: Cc1csc2ccc(F)cc12
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(CCCCl)sc2ccc(F)cc12
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
n-BuLi in heptanes (1.5 ml, 2.4 mmol, 1.6M) was added drop wise to 5-fluoro-3-methyl-benzo[b]thiophene (332 mg, 2.0 mmol) in THF (5 ml) at −20° C. under argon. The reaction mixture was stirred at −15° C. for 30 min, then 1-chloro-3-iodopropane (322 μl, 3.0 mmol) and copper (1) iodide (38 mg, 0.2 mmol) were added. The reaction was stirred at −15° C. for 1 h, then NH4Cl (sat'd aq., 5 ml) was added. The product was extracted with diethyl ether (2×30 ml) and the organic layer was washed with brine (10 ml), dried (K2CO3), filtered and concentrated in vacuo. The product was purified by column chromatography (0–1% diethyl ether in heptanes) to give 2-(3-chloro-propyl)-5-fluoro-3-methyl-benzo[b]thiophene (180 mg, 37%). 1H NMR (CDCl3): δ 2.19 (tt, 2H), 2.22 (s, 3H), 2.94 (t, 2H), 3.57 (t, 2H), 7.04 (dt, 1H), 7.28 (dd, 1H), 7.66 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.CO.[C:13](=O)([O-])[O-:14].[K+].[K+].C(Cl)Cl>CN(C=O)C.O.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:14][CH3:13])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(Br)ccc1C#N
Temperature: 55 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-benzonitrile (15.0 g, 75.0 mmol), methanol (30.4 mL, 350 mmol) and potassium carbonate (31.1 g, 225 mmol) in DMF (150 mL) was stirred under argon at 55° C. overnight. At this point TLC (100% methylene chloride) revealed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dried over Mg2SO4, filtrated, and concentrated under reduced pressure, providing (15.2 g, 95.5%) of 4-bromo-2-methoxy-benzonitrile as a white solid. 1H-NMR (CDCl3) δ 7.41 (d, J=8.1 Hz, 1H), 7.16 (dd, J=8.1, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 3.93 (s, 3H); MS GC-MS (M+=211; RT=6.15 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[CH3:23][NH:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[OH-].[Na+].O.CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:24]([CH3:23])[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:7]=1)[CH3:10]
Reactant: CNC1CCOCC1
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1nc(N(C)C2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Yield: 18 %

Procedure:
A solution of 338 mg (1.0 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 172 mg (1.5 mmol) N-methyl-tetrahydro-2H-pyran-4-amine and 509 μl (3.0 mmol) DIPEA in NMP (1 ml) was heated in the microwave at 180° C. for 2 h. Subsequently the RM was diluted with a 2M aq. NaOH sol, water and EtOAc and the layers were separated. The organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 13:7) provided 77 mg (0.18 mmol, 18%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(methyl-tetrahydro-pyran-4-yl-amino)-pyridine-3-carboxylic acid amide (example 258). [M+H]+ 418.2
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1.[N:25]1[C:33]([NH2:34])=[C:32]2[C:28]([N:29]=[CH:30][NH:31]2)=[N:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:34][C:33]1[N:25]=[CH:26][N:27]=[C:28]2[C:32]=1[N:31]=[CH:30][N:29]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1
Reactant: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(Cn3cnc4c(N)ncnc43)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 64.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2a (200 mg, 0.546 mmol), adenine (81 mg, 0.601 mmol), K2CO3 (83 mg, 0.601 mmol), and DMF (4 mL). The crude product was recrystallized from ethanol (EtOH) to provide 164 mg of a beige solid (65%), mp 281.5-282.7° C. (decomposes). 1H NMR (DMSO-d6) δ: 8.06 (s, 1H); 8.04 (s, 1H); 7.76-7.81 (m, 1H); 7.70-7.76 (m, 1H); 7.60-7.67 (m, 2H); 7.45 (s, 1H); 7.22 (s, 2H); 6.90 (s, 1H); 5.08 (d, J=17 Hz, 1H); 4.91 (d, J=17 Hz, 1H); 3.87 (s, 3H); 3.87 (s, 3H). 13C NMR (DMSO-d6) ppm: 159.9, 156.2, 155.4, 152.9, 150.0, 149.7, 149.4, 143.0, 141.9, 133.7, 132.1, 131.9, 131.2, 130.8, 129.3, 118.4, 113.6, 108.4, 105.8, 56.5, 56.1, 44.7. MS (ES): m/z 464.1 (M+). Anal. calcd. for C22H18ClN7O3.0.1C2H6O.0.05KCl: C, 56.47; H, 3.97; Cl, 7.88; N, 20.76. Found: C, 56.54; H, 4.05; Cl, 7.77; N, 20.55.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CCCCP(=O)O[CH2:34][C:35]([CH3:52])([CH3:51])[CH2:36][N:37]4[CH:41]=[C:40]([B:42]5[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]5)[CH:39]=[N:38]4)=CC=3OC)N=2)=CC=1.[Br:58][C:59]1[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]2[C:75]([C:76]([F:79])([F:78])[F:77])=[CH:74][N:73]=[C:72]([NH:80][C:81]3[CH:92]=[CH:91][C:84]([CH2:85][CH2:86][CH2:87][PH:88](=[O:90])[OH:89])=[CH:83][C:82]=3[O:93][CH3:94])[N:71]=2)=[CH:61][CH:60]=1>>[Br:58][C:59]1[N:64]=[C:63]([C:65](=[O:68])[NH:66][CH3:67])[C:62]([NH:69][C:70]2[C:75]([C:76]([F:79])([F:77])[F:78])=[CH:74][N:73]=[C:72]([NH:80][C:81]3[CH:92]=[CH:91][C:84]([CH2:85][CH2:86][CH2:87][PH:88](=[O:89])[O:90][CH2:34][C:35]([CH3:52])([CH3:51])[CH2:36][N:37]4[CH:41]=[C:40]([B:42]5[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]5)[CH:39]=[N:38]4)=[CH:83][C:82]=3[O:93][CH3:94])[N:71]=2)=[CH:61][CH:60]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F

Procedure:
Prepared analogously to Compound 74A replacing Compound 74B with (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)ethylphosphinic acid (Compound 67B). MS (ESI): m/z 865.86/867.92 [M+H]+. UPLC: tR=1.61 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@@H:12]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[C:25]([F:33])[CH:24]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].CO.C1COCC1.O.NN>O>[NH2:3][C@@H:12]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[C:25]([F:33])[CH:24]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC[C@H](c1ccc(C(F)(F)F)c(F)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC[C@@H](N)c1ccc(C(F)(F)F)c(F)c1
Temperature: 50 °C
Yield: 59.5 %

Procedure:
To a solution of 288 (0.350 g, 0.750 mmol) and MeOH:THF (6 mL, 1:1) was added hydrazine monohydrate (0.188 mL, 3.75 mmol) and the reaction was heated to 50° C. for 4 d. The reaction was then poured into water, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:20) to afford 0.150 g (59.4%) of (R)-tert-butyl 3-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)propylcarbamate (290).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:30])[N:9]([CH3:29])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19](CN(C(C)C)C(C)C)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]2[C:8](=[O:30])[N:9]([CH3:29])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH3:19])=[C:13]([N:12]([CH:6]([CH3:7])[CH3:5])[CH:11]([CH3:15])[CH3:10])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(Cc1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1)C(C)C
Agent: Cl
Solvent: CCO
Product: Cc1oc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)nc1N(C(C)C)C(C)C
Yield: 187.2 %

Procedure:
0.10 g (0.00023 mol) of 7-chloro-3-(4-diisopropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 10 ml of ethanol and treated with 0.063 ml (0.00023 mol) of 3.7N ethanolic hydrochloric acid. The solution was completely freed from the solvents and recrystallized from ethanol/diethyl ether. There was obtained 0.10 g (92%) of 7-chloro-3-(4-diisopropylamino-methyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride as white crystals; m.p. 228°-230°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH:32]=[CH:31][CH:30]=[N:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: c1cn[nH]c1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(Cn4cccn4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and pyrazole were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19](Br)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][S:35]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:37])=[O:36]>CN(C=O)C>[O:5]([C:6]([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([N:43]2[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:36])=[O:37])[CH2:45][CH2:44]2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: CS(=O)(=O)CCN1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCN(CCS(C)(=O)=O)CC2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 100 °C
Yield: 100 %

Procedure:
tert-butyl N-tert butoxycarbonyl-5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-ylcarbamate (75 mg, 0.13 mmol) was dissolved in DMF (1 mL) and 1-(2-(methylsulfonyl)ethyl)piperazine (77 mg, 0.40 mmol) was added. The reaction mixture was heated at 100° C. in a sealed tube overnight. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 and water and the layers separated using a phase separation cartridge. The organic layer was concentrated in vacuo to give the product (84.01 mg, 0.13 mmol)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][C:11]#[N:12])[CH:8]=[CH:9][C:2]1=2.[OH-].[Na+].C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:37][CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=N2)C=1)(C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([CH2:37][CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:11]#[N:12])[CH:8]=[CH:9][C:2]1=2
Reactant: N#CCc1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CC(CC1CCCC1)c1ccc2sccc2c1
Yield: 40.3 %

Procedure:
In a round bottom flask was placed benzo[b]thiophen-5-yl-acetonitrile (700 mg, 4.04 mmol), tetrabutyl ammonium hydrogen sulfate (1.37 g, 4.04 mmol) and a 47% by weight solution of aqueous sodium hydroxide (646 μl, 8.08 mmol). To this well stirred mixture was added iodomethylcyclopentane (prepared in PCT WO 2004/052869 A1 Example 1, 1.69 g, 8.08 mmol) and the vigorously stirred mixture was heated to reflux for 6 h. The reaction was then diluted with water (5 mL) and methylene chloride (10 mL) and extracted with methylene chloride (3×20 mL). The organics were combined and dried over sodium sulfate, filtered and concentrated in vacuo. Purification an AnaLogix Intelliflash system (40 g column, 3% ethyl acetate/hexanes to 5% ethyl acetate/hexanes) afforded 2-benzo[b]thiophen-5-yl-3-cyclopentyl-propionitrile (416 mg, 40%) as a yellow oil: ES-HRMS m/e calcd for C16H17NS (M+H)+ 256.115, observed 256.115.
Reaction SMILES: Br[C:2]1[S:6][N:5]=[CH:4][C:3]=1[N+:7]([O-:9])=[O:8].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.O>O1CCOCC1>[N+:7]([C:3]1[CH:4]=[N:5][S:6][C:2]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([O-:9])=[O:8]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cnsc1Br
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnsc1N1CCOCC1
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4-nitroisothiazole (P) (500 mg, 2.39 mmol) and morpholine (6B2) (620 mg, 7.12 mmol) in dioxane (10 mL) at room temperature (25° C.) was added DIEA (851 μL, 4.78 mmol). The solution was stirred for 30 min and HPLC showed the reaction was complete. Water (10 mL) was then added. A precipitate was formed, filtered and air dried at room temperature to get the product 6C6 (500 mg, 2.32 mmol).
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1)=[O:13])([CH3:10])[C:3](OC(C)(C)C)=[O:4].Cl>O1CCCC1>[CH3:1][C:2]1([CH3:10])[NH:11][C:12](=[O:13])[N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:3]1=[O:4]
Reactant: CSc1ccc(NC(=O)NC(C)(C)C(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CSc1ccc(N2C(=O)NC(C)(C)C2=O)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Compound 114.1 can be prepared by process “A”. To this end, 1.04 g of 4-methylsulfanyl-3-trifluoromethylphenylamine were dissolved in 25 ml of dry acetonitrile. This solution was added dropwise with stirring to a 20% solution, heated to 70° C., of phosgene in toluene, and then stirred at 80° C. for 2 h. The cooled reaction solution was concentrated under reduced pressure, and the residue was taken up with toluene and concentrated again under reduced pressure. Finally, the residue was dissolved in 25 ml of dry tetrahydrofuran and the solution was admixed with stirring with 0.88 g of tert-butyl 2-amino-2-methylpropionate hydrochloride. 1.05 ml of triethylamine were slowly added dropwise to the reaction mixture which was then stirred at room temperature for 4 h. The reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. tert-Butyl 2-methyl-2-[3-(4-methylsulfanyl-3-trifluoromethylphenyl)ureido]propionate (molecular weight 392.13 (C17H23F3N2O3S); retention time Rt=2.40 min. [B]; MS (ESI): 337.26 (MH+−C4H8)) was obtained. The urea was dissolved in 20 ml of tetrahydrofuran, admixed with 4.9 ml of concentrated hydrochloric acid and stirred at 80° C. for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was admixed with ethyl acetate and water. The organic phase was removed, washed with saturated sodium hydrogen-carbonate solution and then with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 96/4 dichloromethane/methanol. 21.2 g (90% yield) of 5,5-dimethyl-3-(4-methylsulfanyl-3-trifluoromethylphenyl)imidazolidin-2,4-dione 114.1 were obtained. Molecular weight 318.06 (C13H13F3N2O2S); retention time Rt=1.93 min. [B]; MS (ES−): 317.07 (M−H+).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+:6].[Na+].[C:8]([OH:19])(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>[Hg].O>[C:8]([O-:19])(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([O-:15])=[O:14])=[CH:11][CH:10]=1.[Na+:6].[Na+:6]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Hg]
Agent: [Na+]
Solvent: O
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
An aqueous solution of 2 (wt)% sodium sulfate, approximately 0.14 moles/liter of water, was used as the pH neutral anolyte. The catholyte consisted of water, terephthalic acid, and sodium hydroxide. The cathode was mercury. The terephthalic acid reacted with the sodium hydroxide to form disodium terephthalate. The pH at the beginning of the electrochemical reaction was 7.2. As the reaction progressed, the pH increased to 12.9 at the end of the electrolysis. No attempt was made to maintain a neutral pH. Results are in Table I.