Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10](Cl)[CH:9]=1)=[O:7].[CH3:30][S-:31].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[C:10]([S:31][CH3:30])[CH:9]=1)=[O:7]
Reactant: COc1cccc2c1ccc1nc3cc(Cl)cc(C(=O)NCCN(C)C)c3nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2c1ccc1nc3cc(SC)cc(C(=O)NCCN(C)C)c3nc12
Temperature: 60 °C
Yield: 42.3 %

Procedure:
A mixture of 9-chloro-4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (85 mg) and sodium thiomethoxide (43 mg) in N,N-dimethylformamide (1 mL) was heated to 120° C. for 6 hours and 60° C. for 16 hours. The reaction mixture was then cooled, diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid which was purified using flash chromatography to yield the desired title compound (37 mg).
Reaction SMILES: C(OC1C=CC([C@@H](O)CNCCC2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=C2C=1NC(=O)C=C2)C1C=CC=CC=1.[CH2:67]([O:74][C:75]1[CH:76]=[CH:77][C:78]([C@@H:86]([O:136][Si](C(C)(C)C)(C)C)[CH2:87][NH:88][C:89]([CH3:135])([CH3:134])[CH2:90][C:91]2[CH:92]=[C:93]([CH:131]=[CH:132][CH:133]=2)[C:94]([N:96]([CH2:98][C:99]2[CH:100]=[C:101]([S:105]([C:108]3[CH:109]=[C:110]4[C:115](=[C:116]([CH3:118])[CH:117]=3)[N:114]=[CH:113][C:112]([C:119]([NH2:121])=[O:120])=[C:111]4[NH:122][C:123]3[CH:128]=[CH:127][CH:126]=[C:125]([O:129][CH3:130])[CH:124]=3)(=[O:107])=[O:106])[CH:102]=[CH:103][CH:104]=2)[CH3:97])=[O:95])=[C:79]2[C:84]=1[NH:83][C:82](=[O:85])[CH:81]=[CH:80]2)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>>[CH2:67]([O:74][C:75]1[CH:76]=[CH:77][C:78]([C@@H:86]([OH:136])[CH2:87][NH:88][C:89]([CH3:134])([CH3:135])[CH2:90][C:91]2[CH:92]=[C:93]([CH:131]=[CH:132][CH:133]=2)[C:94]([N:96]([CH2:98][C:99]2[CH:100]=[C:101]([S:105]([C:108]3[CH:109]=[C:110]4[C:115](=[C:116]([CH3:118])[CH:117]=3)[N:114]=[CH:113][C:112]([C:119]([NH2:121])=[O:120])=[C:111]4[NH:122][C:123]3[CH:128]=[CH:127][CH:126]=[C:125]([O:129][CH3:130])[CH:124]=3)(=[O:107])=[O:106])[CH:102]=[CH:103][CH:104]=2)[CH3:97])=[O:95])=[C:79]2[C:84]=1[NH:83][C:82](=[O:85])[CH:81]=[CH:80]2)[C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CN(C)C(=O)c5cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)c5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CN(C)C(=O)c5cccc(CC(C)(C)NC[C@H](O)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 144, using Intermediate 143 as a substrate. ES/MS calcd. for C55H54N6NaO8S+ 981.4. Found m/z=981.4 (M+Na)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([OH:51])=O)[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[CH2:53]([CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[CH2:53]([CH:60]1[CH2:65][CH2:64][N:63]([C:49]([C:47]2[N:48]=[C:43]3[CH2:42][CH2:41][CH:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([O:32][CH3:31])=[C:34]([CH3:52])[CH:35]=4)[CH2:45][N:44]3[CH:46]=2)=[O:51])[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCC(Cc5ccccc5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 4-benzylpiperidine (116 μl; 116 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered out. Yield: 182 mg (81%)
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:17])=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nn1nc(-c2cccs2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2cccs2)c2ccccc2c1=O

Procedure:
The product of Example 10B and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 10C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (s, 1H), 8.40 (ddd, J=7.7, 1.6, 0.8 Hz, 1H), 8.17 (ddd, J=8.1, 1.3, 0.6 Hz, 1H), 8.04 (ddd, J=8.0, 7.2, 1.6 Hz, 1H), 7.98 (ddd, J=7.8, 7.2, 1.3 Hz, 1H), 7.81 (dd, J=5.1, 1.1 Hz, 1H), 7.65 (dd, J=3.6, 1.1 Hz, 1H), 7.35-7.47 (m, 4H), 7.28 (dd, J=5.1, 3.6 Hz, 1H), 3.72 (s, 2H); MS (APCI) M/Z 396 (M+H)+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: BrCCCCOC1CCCCO1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
3,4-Dihydro-2H-pyran (8.5 mL, 90.96 mmol) was added dropwise to the dichloromethane (20 mL) solution of 51 (10.7 g, 69.93 mmol) and p-toluenesulfonic acid monohydrate (26.5 mg, 0.1372 mmol). The mixture was stirred at room temperature over night. After removing the solvent, the residue was purified by flash chromatography on silica gel with 5:1 hexanes/ethyl acetate as the eluent to yield product 52 as a colorless oil (15.3 g, 92%). 1H NMR (400 MHz, CDCl3): δ 1.48-1.62 (m, 4H), 1.68-1.85 (m, 4H), 1.94-2.02 (m, 2H), 3.40-3.53 (m, 4H), 3.74-3.88 (m, 2H), 4.57-4.59 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6](OC(C)C)=[O:7].O.[CH2:34]([NH2:36])[CH3:35]>>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([NH:36][CH2:34][CH3:35])=[O:7]
Reactant: CCN
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Solvent: O
Product: CCNC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of isopropyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(d)) (0.2 g, 0.45 mmol, 1.0 eq) in ethylamine (6 mL, 60-70% aqueous solution) was stirred at 100° C. overnight in a sealed tube. The reaction mixture was then cooled to room temperature and poured into water. The mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 1:20 to 1:4, v/v) to give the title compound as a white solid (0.15 g, 80%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([CH3:28])[C@H:5]([NH:7][C:8]1[C:9]2[N:10]([CH:17]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:19]=2)[N:11]=[CH:12][C:13]=1[C:14](=[O:16])[NH2:15])[CH3:6].[OH-].[K+].Cl>CO.O>[C:14]([C:13]1[CH:12]=[N:11][N:10]2[CH:17]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:19]=[C:9]2[C:8]=1[NH:7][C@H:5]([CH3:6])[C:4]([CH3:29])([CH3:28])[C:3]([OH:30])=[O:2])(=[O:16])[NH2:15]
Reactant: COC(=O)C(C)(C)[C@@H](C)Nc1c(C(N)=O)cnn2cc(-c3ccc(OC)nc3)cc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc3c(N[C@H](C)C(C)(C)C(=O)O)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
(R)-methyl-3-((3-carbamoyl-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-2,2-dimethylbutanoate (125 mg, 0.304 mmol) was dissolved in MeOH (25 mL) and water (1.0 mL). Potassium hydroxide (256 mg, 4.56 mmol) was added and the reaction mixture was heated at reflux overnight. After completion, the reaction mixture was cooled to room temperature and MeOH was removed under reduced pressure. The crude mass obtained was acidified to pH 5 at 0° C. using 1.5N HCl and stirred at room temperature for 15 minutes to give a solid that was collected by vacuum filtration and dried to afford the title compound (100 mg, 0.252 mmol, 83% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.13-1.15 (d, J=8.4 Hz, 6H), 1.25-1.26 (d, J=6.4 Hz, 3H), 3.86 (s, 3H), 4.68 (m, 1H), 6.84-6.86 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 8.06-8.064 (d, J=2 Hz, 1H), 8.15-8.18 (d, J=12 Hz, 2H), 8.59 (s, 1H), 10.86-10.89 (d, J=10 Hz, 1H). [α]24.8=1.6 (c=0.1, MeOH)
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(OCC)(=O)C>[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=C[C@@H](O)CC1=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCC1=C[C@@H](OC2CCCCO2)CC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 1.74 parts of methyl 7-(3(S)-hydroxy-5-oxocyclopent-1-en-1-yl)heptanoate in 12 parts by volume of dry benzene is added 0.005 part of p-toluenesulfonic acid and 1.74 parts of dihydropyran. The reaction mixture is stirred for 5 minutes under a nitrogen atmosphere and then allowed to stand at room temperature for a further 2 hours. The resulting solution is diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and stripped of solvent under reduced pressure to afford methyl 7-(3(S)-tetrahydropyran-2-yloxy-5-oxocyclopent-1-en-1-yl)-heptanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[Br:13]Br>>[Br:13][C:11]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Product: O=[N+]([O-])c1cc(Br)c2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.5 %

Procedure:
To a solution of 5-nitroindoline (from Aldrich, 2.0 g, 12.2 mmol) in 15 mL of ACOH was added Br2 (1.0 mL, 19.4 mmol) in a portion and the resulting solution was stirred for 1 h at 25° C. Reaction mixture was concentrated in vacuo, yielding a yellow solid (3.9 g, >95%) of the desired product as a HBr salt, which was subjected to the following reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)O)c(O)c1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(O)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-hydroxy-4-methylbenzoic acid (5.00 g) in acetic acid (70.0 mL) was added dropwise bromine (1.68 mL), and the mixture was stirred at room temperature for 5.5 hr. To the reaction mixture was added water, and the precipitate was collected by filtration, and dried under reduced pressure to give the title compound (6.78 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:12]Br>O>[Br:12][CH:4]([C:3](=[O:10])[CH:2]([CH3:1])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: BrBr
Solvent: O
Product: CCOC(=O)C(Br)C(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a 0° C. solution of ethyl 4-methyl-3-oxopentanoate (5.0 mL, 31 mmol) in water (20 mL) was added bromine (16 mL, 31.3 mmol) via syringe pump (0.5 hour). The mixture was stirred at 0° C. for 0.5 hour. The solution was extracted with EtOAc (3×20 mL). The organic extracts were combined, extracted with brine (2×60 mL), dried over MgSO4, filtered, evaporated, and dried in vacuo, affording ethyl 2-bromo-4-methyl-3-oxopentanoate (6.0 g, 82% yield). The product was used without further purification.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:54]([NH:56][C@H:57]([C:63]([OH:65])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61])=[O:55])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30].C(N(CC)CC)C>CN(C)C=O>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:7]([NH:27][C@H:28]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:54]([NH:56][C@H:57]([C:63]([OH:65])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61])=[O:55])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:47])[CH3:48])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])[C@H:29]([CH2:31][CH3:32])[CH3:30])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.69 Gram of Z-Leu-OSu, the above-obtained H-Ile-Leu-Leu-Ala-Gln-OH and 0.22 ml of triethylamine were dissolved in 50 ml of dimethylformamide, and the mixture was stirred at a room temperature for 20 hours. After removal of dimethylformamide by distillation, 1N-succinic acid was added to the residue, the precipitated material was collected by filtration and washed with water until the filtrate become neutral and then dried. The dried material was washed with hot methanol to obtain 1.10 g of Z-Leu-Ile-Leu-Leu-Ala-Gln-OH.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Zn]>[C:15]1([C:12]2[O:13][CH:14]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[N:11]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(-c2coc(-c3ccccc3)n2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(-c2coc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
zinc dust (0.59 ml, 64 mmol) was added to a mixture of 4-(4-nitrophenyl)-2-phenyloxazole (1.13 g, 4.2 mmol) in acetic acid (20 ml, 349 mmol) at room temperature. An exotherm resulted. The reaction mixture was stirred at room temperature for 60 minutes then filtered, rinsing with ethyl acetate, and the filtrate concentrated under reduced pressure. The concentrate was slurried in toluene and concentrated under reduced pressure to afford a yellow solid (1.0 g, quantitative). ESI+ m/z=237.1 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:17](SC)[C:18]#[N:19]>[Ni].O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]#[N:19]
Reactant: CSC(C#N)c1cccc(C(=O)c2ccc(Cl)cc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: N#CCc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A 280 g sample of a commercial Raney nickel preparation was washed twice with water, titrated to a pH of 7 with acetic acid, washed twice with water and three times with tetrahydrofuran. The Raney nickel preparation was then slurried in 300 ml of tetrahydrofuran and added to a stirred solution of 34.4 g (0.11 mole) of 2-amino-3-(4-chlorobenzoyl)-α-(methylthio)benzeneacetonitrile in 250 ml of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 10 minutes, filtered through Celite, and the filtrate concentrated to give a solid as a residue. This solid residue was recrystallized from acetonitrile to yield 16.4 g (56%) of the titled compound as brown crystals, m.p. 181°-2° C.
Reaction SMILES: [OH:1][C:2]1([C:14]([O:16]C)=[O:15])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O[Li].O>>[OH:1][C:2]1([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(O)CCCc2c(C)cc(C)cc21
Agent: [Li]O
Solvent: O
Product: Cc1cc(C)c2c(c1)C(O)(C(=O)O)CCC2

Procedure:
Prepared according to the method described in Example 1(ii) from 1-hydroxy-5,7-dimethyltetralin-1-yl-carboxylic acid, methyl ester (1.24 g; 5.27 mmol; from step (i) above) and LiOH.H2O (0.443 mg; 10.6 mmol). Yield 0.629 g (50%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH2:55][CH:56]([NH2:58])[CH3:57])[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]>CN(C=O)C>[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH2:55][CH:56]([NH:58][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH3:57])[CH:50]=[CH:51][C:52]=1[O:53][CH3:54]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1ccc(CC(C)N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(CC(C)NC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1OC
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-(3,4-dimethoxyphenyl)-1-methylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2-(3,4-dimethoxyphenyl)-1-methylethyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.23 min, MH+ 472.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.Cl.[F:21][C:22]1([F:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)C(C)C)C>O1CCCC1>[F:21][C:22]1([F:28])[CH2:27][CH2:26][N:25]([C:3]2[N:8]=[CH:7][N:6]=[C:5]([N:9]3[C:13](=[O:14])[C:12]([N:15]4[CH:19]=[CH:18][N:17]=[N:16]4)=[CH:11][NH:10]3)[CH:4]=2)[CH2:24][CH2:23]1
Reactant: FC1(F)CCNCC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(N2CCC(F)(F)CC2)ncn1

Procedure:
250 mg (0.8 mmol) of the compound from Example 12A, 158 mg (1.0 mmol) of 4,4-difluoropiperidine hydrochloride and 435 μl (323 mg, 2.5 mmol) of N-ethyl-N-(propan-2-yl)propane-2-amine are initially charged in 5 ml of tetrahydrofuran and reacted in a single mode microwave (Emrys Optimizer) at 120° C. for 30 min. After pre-purification by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient), the product is additionally purified by column chromatography on silica gel (mobile phase dichloromethane/methanol, 10/1). Yield: 29 mg (10% of theory)
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:34]([NH:41][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[N:33][C:25]=1[S:24][CH2:23][CH2:22][S:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:20])=[O:21])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
132 mg (0.81 mmol) of CDI were added to a solution of 250 mg (0.77 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (6 ml), and the mixture was stirred for 1 h at RT. A solution of 82 mg (0.77 mmol) of benzylamine in DCM (6 ml) was then added, and stirring was continued for a further 16 hours at RT. The reaction solution was then washed in each case three times with a sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 266 mg (0.64 mmol, 83%) of N-benzyl-2-(2-(phenylsulfonyl)ethylthio)nicotinamide were obtained as residue.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[Br:18]Br>C(Cl)(Cl)Cl.ClCCl>[Br:18][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:11])[CH3:1])[C:7]#[N:8]
Reactant: BrBr
Reactant: CN(C)c1ccc(C#N)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)c1ccc(C#N)cc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-(dimethylamino)benzonitrile (2.19 g) in chloroform (15 mL) was added pyridine (1.2 mL) and a solution of bromine (0.75 mL) in chloroform (15 mL) dropwise over 45 minutes. Upon complete addition, the mixture was stirred for a further 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water, brine and evaporated to afford a yellow oil of 3-bromo-4-dimethylaminobenzonitrile which was dissolved in tetrahydrofuran (25 mL). Meanwhile, a stirred solution of diisopropylamine (2.7 mL) in tetrahydrofuran (50 mL), at −15° C. and under nitrogen, was treated with a solution of n-butyllithium in hexanes (7.70 mL, 2.5M) over 30 minutes, whilst maintaining the temperature below −10° C. After stirring for 30 minutes the mixture was treated with methylpyrazine (1.21 g) over 15 minutes, then stirred for 1 hour. The solution of 3-bromo-4-(dimethylamino)benzonitrile was added over 1 hour, keeping the temperature below −10° C. The reaction mixture was allowed to warm to room temperature over 2 hours, then stood overnight, then treated with water (10 mL). The tetrahydrofuran was removed in vacuo and the resultant mixture was treated with a mixture of water and ethyl acetate (1:1 v/v) and the mixture stirred for 15 minutes. The resultant precipitate was collected by filtration and washed thoroughly with water/ethyl acetate (1:1 v/v) to afford the title compound as a yellow solid (1.0 g). TLC: RF=0.41 (ethyl acetate).