Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.O[CH2:25][C:26]1[C:27]([CH3:37])=[N+:28]([O-:36])[C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]4[C:27]([CH3:37])=[N+:28]([O-:36])[C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(CO)ccc(C(F)(F)F)[n+]1[O-]
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)ccc(C(F)(F)F)[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a suspension of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (64 mg, 0.2 mmol), 3-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)pyridine 1-oxide (41 mg, 0.2 mmol) and Ph3P (105 mg, 0.4 mmol) in anhydrous THF (3 mL) at room temperature was added dropwise a 40% solution of DEAD in toluene (0.091 mL, 0.4 mmol). The resulting clear, yellowish solution was then stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, then saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (40-100%) in hexanes to afford 70 mg (69%) of the title compound as a light yellow foam. A portion of the product (10 mg) was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 7.2 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.33 min, [M+H]+=512.0.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[C@H:15]([CH2:21][N:22]3C(=O)C4C(=CC=CC=4)C3=O)[NH:14][CH2:13][C:12]=2[S:11][C:10]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].NN>C(O)C>[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[C@H:15]([CH2:21][NH2:22])[NH:14][CH2:13][C:12]=2[S:11][C:10]=1[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)[C@H](CN1C(=O)c3ccccc3C1=O)NC2
Agent: Cl
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)[C@H](CN)NC2
Temperature: 80 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a solution of the above 2-benzyloxy-carbonylamino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride (42 mg, 0.072 mmol) in ethanol (0.5 ml) was added hydrazine (68 μl, 0.22 mmol). The solution was stirred at 80° C. for 5 hours and at room temperature for 16 hours. The mixture was filtered and the filtrate evaporated in vacuo. The residue was extracted with dichloromethane (5×1 ml). The combined dichloromethane washes were evaporated in vacuo affording 20 mg (67%) of 5-(S)-aminomethyl-2-benzyloxy-carbonylamino-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1)([O-])=O.O.O.[Sn](Cl)Cl.Cl.[OH-].[Na+]>CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:34](=[O:35])[C:13]2=[CH:14][N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[CH:25][CH:24]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:12]2=[N:11]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Nitrophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 427, 0.50 g, 1.1 mmol) was dissolved in methanol (20 mL) and treated with tin(II) chloride dihydrate (1.2 g, 5.4 mmol, 5 equiv) and hydrochloric acid (0.18 mL, 6 M aqueous, 1.1 mmol, 1 equiv). The mixture was placed into a preheated oil bath at 45° C. for 2 hours, cooled to ambient temperature and the pH of the mixture was brought to ˜pH 7 by addition of sodium hydroxide (1 N aqueous). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.17 (1H, s), 8.46 (1H, d, J=2.3 Hz), 8.23 (1H, d, J=7.8 Hz), 7.83 (2H, d, J=8.5 Hz), 7.79 (1H, d, J=8.8 Hz), 7.72 (1H, br s), 7.62 (1H, t, J=7.4 Hz), 7.54 (1H, t, J=7.5 Hz), 7.46 (2H, d, J=8.6 Hz), 7.33 (1H, d, J=7.6 Hz), 7.10 (1H, t, J=7.7 Hz), 6.87 (1H, d, J=8.1 Hz), 6.70 (1H, t, J=7.5 Hz), 6.53 (1H, br m), 5.80 (1H, br s), 5.76 (2H, s), 5.19 (1H, br s) ppm; high resolution mass spectrometry (ES+) m/z 433.0 [(M+H)+; calculated for C26H21N6O: 433.2].
Reaction SMILES: FC(F)(F)C=O.[CH:7]1([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]([O:27][CH3:28])=[O:26])[C@@H:20]([CH3:29])[CH2:19][N:18]4[C:30]([O:32][CH:33]3[CH2:37]CC[CH2:34]3)=[O:31])[CH:12]=[N:11]2)[CH2:9][CH2:8]1.ClC(OC(C)C)=O>>[CH:7]1([N:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]([C:25]([O:27][CH3:28])=[O:26])[C@@H:20]([CH3:29])[CH2:19][N:18]4[C:30]([O:32][CH:33]([CH3:37])[CH3:34])=[O:31])[CH:12]=[N:11]2)[CH2:8][CH2:9]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(C(=O)OC2CCCC2)C[C@@H]1C
Agent: CC(C)OC(=O)Cl
Agent: O=CC(F)(F)F
Product: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
(S)-4-isopropyl 1-methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate was prepared from 2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone following the procedure outlined above for (S)-4-cyclopentyl 1-methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate and substituting isopropyl chloroformate (1.0 M solution in toluene) in Step 1. The desired product was obtained as an off-white solid (0.065 g, 79%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90-1.03 (m, 2 H), 1.07 (br d, J=6.16 Hz, 5 H), 1.26 (dd, J=5.86, 2.93 Hz, 6 H), 3.60-3.83 (m, 6 H), 4.49-4.71 (m, 1 H), 4.93 (dt, J=12.46, 6.08 Hz, 1 H), 7.28 (br d, J=7.04 Hz, 1 H), 7.65-7.87 (m, 3 H), 8.14 (s, 1 H). MS (ESI, pos. ion) m/z 399 [M+1]+.
Reaction SMILES: C(OC(NCCCCCC(O)=O)=O)(C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]=[C:48]=[O:49])=[O:40])([CH3:37])([CH3:36])[CH3:35].[F:50][C:51]1[C:52](=[O:58])[NH:53][C:54](=[O:57])[NH:55][CH:56]=1>C1C=CC=CC=1.C(N(CC)CC)C>[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([N:55]1[CH:56]=[C:51]([F:50])[C:52](=[O:58])[NH:53][C:54]1=[O:57])=[O:49])=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCCCCN=C=O
Agent: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NCCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 6-t-butoxycarbonylaminohexanoic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 5-t-butoxycarbonylaminopentyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-(5-t-butoxycarbonylaminopentyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 20.
Reaction SMILES: N[C@H](C(O)=O)CCC(=O)N.N[C@H](C(O)=O)CC(=O)N.N[C@H](C(O)=O)CCCNC(=N)N.NCC(O)=O.[NH2:37][C@@H:38]([C:49]([OH:51])=[O:50])[CH2:39][C:40]1[CH:45]=[CH:44][C:43](OCC)=[CH:42][CH:41]=1.N[C@H](C(O)=O)CS.N(CC(O)=O)C>>[NH2:37][C@H:38]([C:49]([OH:51])=[O:50])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOc1ccc(C[C@@H](N)C(=O)O)cc1
Agent: CNCC(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Gln 0.87; Asn 1.00; Arg 0.99; Gly 0.96 (Mca, DTyr(Et), Cys and Sar were not determined)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:22]([C:21]2[C:20]([CH3:19])=[N:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[4-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [O:1]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C@:23]([OH:31])([CH2:29][OH:30])[CH2:24]2)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[C:40](Cl)=[O:41])=[CH:35][CH:34]=1>N1C=CC=CC=1>[O:1]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH2:21][CH2:22][C@@:23]([CH2:29][O:30][C:40](=[O:41])[N:39]([C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1)[C:43]1[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=1)([OH:31])[CH2:24]2)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)N(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(CO)C2)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(COC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1)C2)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
A mixture of (2R)-5-t-butyldiphenylsiloxy-2-hydroxy-2-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalene (0.49 g) and N,N-di(4-fluorophenyl)carbamoyl chloride (1.08 g) in pyridine (2.3 ml) was stirred at 100° C. for 1.5 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N-HCl, and evaporated in vacuo. The residue was purified by chromatography on silica gel (50 ml) using a mixture of AcOEt and n-hexane to give (2R)-5-t-butyldiphenylsiloxy-2-{[N,N-di(4-fluorophenyl)-carbamoyloxy]methyl}-2-hydroxy-1,2,3,4-tetrahydronaphthalene (0.356 g) as an oil.
Reaction SMILES: [CH2:1]([N:8](C)[C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24][NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=1)=[O:27])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24][NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:35]2[N:39]([CH3:40])[N:38]=[N:37][N:36]=2)[CH:32]=[C:31]([CH2:41][CH3:42])[CH:30]=1)=[O:27]
Reactant: CCc1cc(NC(=O)NC[C@@H]2CN(CCc3ccc(F)cc3)CC[C@H]2N(C)Cc2ccccc2)cc(-c2nnnn2C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(NC(=O)NC[C@@H]2CN(CCc3ccc(F)cc3)CC[C@H]2NC)cc(-c2nnnn2C)c1
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A solution of trans-1-{4-(benzyl-methylamino)-1-[2-(4-fluorophenyl)-ethyl]-piperidin-3-ylmethyl}-3-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea (95 mg, 162 μmol) in methanol (20 mL) was combined with Pearlman's catalyst (20% palladium hydroxide on charcoal, 100 mg) and shaken under a hydrogen atmosphere (60 psig) for 15 hours. The mixture was filtered through Celite and the solids were washed with methanol. The filtrate was concentrated under vacuum to provide a pale tan solid (78 mg, 97%). 1H NMR (300 MHz, CDCl3) δ7.78 (s, 1H), 7.36 (s, 1H), 7.16 (m, 2H), 7.13 (s, 1H), 6.96 (t, J=9 Hz, 2H), 4.14 (s, 3H), 3.66 (m, 1H), 3.4-3.1 (m, 4H), 2.95 (s, 3H), 2.9-2.3 (m, 12H), 2.18 (m, 2H), 1.22 (t, J=8 Hz, 3H). Mass spec (ES+) m/z 495.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=2[N:9]=[CH:8]1.[NH:32]([C:34]([CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1)=[O:35])[NH2:33].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:25]=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([NH:33][NH:32][C:34]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[O:35])=[O:17])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(C(=O)O)ccc43)cc2OC)cn1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C(=O)NNC(=O)C5CCN(C(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
To a solution of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carboxylic acid (0.30 g, 0.72 mmol) in dichloromethane was added tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (0.24 g, 0.98 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (0.34 g, 0.89 mmol), diisopropylamine (0.19 g, 1.47 mmol). The resulting mixture was allowed to stir at room temperature. After 16 h, the mixture was concentrated and the residue was purified by silica gel chromatography (2% methanol/dichloromethane elute) to afford 0.30 g (65%) tert-butyl 4-(2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]2)[CH:2]=[CH2:3].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:18][CH2:3][CH:2]1[O:17][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:1]1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[CH:7]3
Reactant: C=CCc1cc(C)c2[nH]c(=O)c(C)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Temperature: 75 °C
Reaction time: 0.42 h
Yield: 65.4 %

Procedure:
To 6-allyl-5-hydroxy-3,8-dimethylcarbostyril (3.86 g, 16.68 mmol), N-bromsuccinimide (3.0 g, 16.68 mmol) and chloroform (140 ml) were added, and stirred for 25 minutes in a bath at 75° C. After cooling, the mixture was washed with water, dried, and condensed. The resultant residue was subjected to recrystallization (chloroform-methanol-ether) to obtain 3.36 g of the title compound as pale yellow prisms (64.7%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Fc1ccccc1Br
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1ccccc1F)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromofluoro benzene. White solid. MS (ESI): 409.2 (MH+)
Reaction SMILES: CC1(O)C2CC3CC(CC1C3)C2.C(OC(=O)C(C)=C)(=O)C(C)=C.[CH2:24]([N:26](CC)[CH2:27]C)C.C[C:32]1(C)[N:37]([O])[C:36](C)(C)[CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[CH3:24][N:26]([C:36]1[CH:35]=[CH:34][CH:33]=[CH:32][N:37]=1)[CH3:27]
Reactant: CCN(CC)CC
Reactant: CC1(C)CCCC(C)(C)N1[O]
Agent: C=C(C)C(=O)OC(=O)C(=C)C
Agent: CC1(O)C2CC3CC(C2)CC1C3
Solvent: Cc1ccccc1
Product: CN(C)c1ccccn1
Yield: 40 %

Procedure:
A glass flask equipped with a stirrer, two dropping funnels, a thermometer and a Dimroth condenser was charged with 16.6 g (0.1 mol) of 2-methyl-2-adamantanol, 23.1 g (0.15 mol) of methacrylic anhydride of 97% purity which is obtained by the process of example 1, 15.7 g (0.155 mol) of triethylamine, 0.6 g (0.005 mol) of dimethylaminopyridine, 70 ml of toluene and 0.005 g of HO-TEMPO, and the mixture was heated and stirred at 50° C. for 31 hours. It was confirmed that 2-methyl-2-adamantyl methacrylate was formed in the reaction mixture in a yield of about 40%. The resultant 2-methyl-2-adamantyl methacrylate was chromatographed on silica gel to obtain 9.1 g of 2-methyl-2-adamantyl methacrylate.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH3:14].CO.[OH-].[Na+].Cl>O>[CH3:14][C:5]1[CH:6]=[C:7]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1ccc(C2(C)CC2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2(C)CC2)ccc1C(=O)O
Temperature: 80 °C
Yield: 85.1 %

Procedure:
2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid methyl ester (2.75 g, 13.46 mmol) was treated with methanol and 5 M aqueous sodium hydroxide solution (20.46 ml, 102.32 mmol). This solution was heated to 80° C. for 4 hours. The reaction mixture was concentrated until methanol was evaporated. A white solid was obtained. The solid was dissolved in 50 ml water under heating then cooled with an ice bath; acidified with 10 ml conc. hydrochloric acid. A white precipitate was formed; filtered; washed with water; dried under high vacuum over night to yield 2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid (2.18 g, 11.46 mmol) MS (ESI) 189.1 (M-H)−
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)[N:13]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH:14]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: COC(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1

Procedure:
4-[2-(4-Bromo-benzyl)-1H-imidazol-4-yl]-benzoic acid methyl ester (12.3 g, 33 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 4-[2-(4-bromo-benzyl)-1-(4-Nitro-phenyl)-1H-imidazol-4-yl]-benzoicacid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:30][N:31]([CH3:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:36]=[CH:37][C:32]([N:31]([CH3:41])[CH3:30])=[CH:33][CH:34]=3)=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccc(N(C)C)cc2)cc1F
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To a stirred solution of (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2, 173 mg) in 1,2-dimethoxyethane (8 ml) were added PdCl2(dppf) (34 mg), an aqueous 10% solution of Na2CO3 (2 ml) and 4-dimethylaminophenylboronic acid (378 mg). The mixture was then stirred at 85° C. under an argon atmosphere for 1.5 h. After cooling to rt, the mixture was diluted with ethyl acetate (15 ml) and washed with water (10 ml). The aqueous layer was extracted with ethyl acetate and the combined organics were washed with water and brine, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (silica gel, gradient cyclohexane=>cyclohexane/ethyl acetate 2:3) to give (RS)-N-(4-cyano-benzyl)-2-(4′-dimethylamino-3-fluoro-biphenyl-4-yl)-2-methoxy-acetamide (167 mg) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32]C)[CH2:28][CH2:27]1)=O)(C)(C)C>>[CH3:24][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:28][CH2:27]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: CN1CCC(Nc2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 18 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester as described in Example 2 to give the title compound (18% yield). LC-RT 2.20 min.; MS 334 (M+H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][CH:3]1[NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.Cl[C:27]1[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>CS(C)=O>[F:8][C:5]1([F:7])[CH2:4][CH:3]([NH:9][S:10]([C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:2]([NH:1][C:27]2[CH:32]=[N:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)[CH2:6]1
Reactant: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)S(=O)(=O)NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1
Temperature: 120 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-methylpropane-2-sulfonamide (66 mg, 0.26 mmol) in DMSO (650 μl) was added DIPEA (135 μl, 0.77 mmol) and 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 47 mg, 0.26 mmol). The reaction mixture was sealed and heated at 120° C. for 18 hours then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 10-60% ethyl acetate/petrol) to afford the title compound.