Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:22])[N:7]2C1C(Cl)=CC=CC=1Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([CH3:33])[CH:25]=1.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)CCC1=O>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:22])[NH:7]3)=[C:26]([CH3:33])[CH:25]=1
Reactant: COc1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Reactant: Cc1cc(F)ccc1B(O)O
Agent: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COc1cc2c(c(-c3ccc(F)cc3C)c1)CCC(=O)N2

Procedure:
1-2,6-Dichlorophenyl)-3,4-dihydro-5-(4-fluoro-2-methylphenyl)-7-methoxy-2(1H)-quinolinone was prepared from 5-bromo-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 1) and 4-fluoro-2-methylphenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 430.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.50 (m, 2H); 7.36 (m, 1H); 7.17 (m, 1H); 6.98 (m, 2H); 6.45 (s, 1H); 5.89 (s, 1H); 3.69 (s, 3H); 2.72 (m, 4H); 2.15 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][CH3:13].[C:14](O)(=[O:16])[CH3:15].Br>O>[CH2:11]([C:4]1[C:5]([OH:9])=[C:6]([C:14](=[O:16])[CH3:15])[CH:7]=[CH:8][C:3]=1[OH:2])[CH2:12][CH3:13]
Reactant: CCCc1c(OC)cccc1OC
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: CCCc1c(O)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
1,3-Dimethoxy-2-propylbenzene (0.90 g, 5.0 mmol), glacial acetic acid (150 ml), and 48% aqueous hydrobromic acid (15 ml, 133 mmol) were combined and stirred at reflux temperature for three days. The mixture was allowed to cool to room temperature; poured into water (500 ml), and the aqueous solution extracted with ether (500 ml, 2×). The ether layers were combined, washed with brine, dried over magnesium sulfate, filtered and taken to dryness in vacuo. Flash chromatography as in Example 10 (plus an additional step of 5% ethyl acetate in hexane) yielded the title product: n.m.r.: δ12.97 (s, 1H), 7.52 (d, 1H), 6.38 (d, 1H), 5.79 (s, 1H), 2.63 (t, 2H), 2.56 (s, 3H), 1.58 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[F:18][C:19]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][NH:39][CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH2:23]1.C=O>CO>[F:18][C:19]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][N:39]([CH3:2])[CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:26][CH2:27]1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CNCC4)CC2)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: C=O
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CN(C)CC4)CC2)c(F)c1
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (9.7 mg, 0.046 mmol) was added to a solution of DIPEA (8 μL, 0.046 mmol), 2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.1 mg, 0.023 mmol) and formaldehyde (1.9 μL, 0.023 mmol) in MeOH (229 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.1 mg, 97%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.3 Hz, 6H), 1.88-1.99 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.04 (m, 3H), 3.08 (br s, 4H), 3.35-3.53 (m, 3H), 3.76 (br s, 4H), 4.10-4.19 (m, 1H), 4.20-4.40 (m, 3H), 6.64-6.69 (m, 1H), 6.74 (dd, J=12.8, 2.1 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 430.4.
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[NH:4][C:3]1=[O:13].S(=O)(=O)(O)O.[N+:20]([O-])([OH:22])=[O:21]>O>[F:14][C:2]1([F:1])[O:7][C:6]2[CH:8]=[C:9]([F:12])[C:10]([N+:20]([O-:22])=[O:21])=[CH:11][C:5]=2[NH:4][C:3]1=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C1Nc2ccc(F)cc2OC1(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Nc2cc([N+](=O)[O-])c(F)cc2OC1(F)F
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
2,2,7-trifluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.5 g, 12.31 mmol) was dissolved in sulfuric acid (40 ml, 750 mmol). The reaction mixture was cooled to 0-5° C. Slowly nitric acid (1.761 ml, 39.7 mmol) was added dropwise and the temperature was maintained between 0-5° C. The reaction mixture was stirred for 30 min at this temperature. Then the reaction mixture was added dropwise to vigorously stirred cold water. A solid was formed, extraction with Dichloromethane. The combined extracts were dried over Na2SO4, and concentrated to yield 2.56 g of the title compound as brown solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc2nc(N3CCN(C(=O)OC(C)(C)C)CC3)sc2c1
Temperature: 25 °C

Procedure:
The ethyl 2-bromobenzo[d]thiazole-6-carboxylate (11.1 g), BOC-piperazine (9.03 g), potassium carbonate (11.7 g) and acetonitrile (400 mL) were combined and heated to reflux overnight. The resulting mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organics were concentrated to a yellow solid, which was recrystallized from EtOAc/heptane to yield a ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzo[d]thiazole-6-carboxylate as a white powder, which was collected by filtration.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH2:29])[CH2:27][OH:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[OH:28][CH2:27][C@@H:26]([NH:29][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@H](CO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@H](CO)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (S)-(+)-phenylglycinol and DIEA to give 2-((S)-2-hydroxy-1-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 376 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:36][C:28]([NH:27][C:23](=[O:24])[CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1)([CH3:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NC(C)(C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), tert-butyl 2-amino-2-methylpropanoate hydrochloride (27.8 mg, 0.142 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction mixture was stirred at 60° C. for 1.5 h and 1M HCl was added to neutralize the reaction solution. The resulting mixture was purified by HPLC to give the title compound. LCMS m/z=479.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.9 Hz, 0.4H), 1.37 (s, 6H), 1.41 (s, 9H), 1.46 (d, J=6.5 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.45 (t, J=7.8 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.05-3.22 (m, 4H), 3.39-3.48 (m, 1H), 3.53-3.62 (m, 1H), 3.72-3.82 (m, 1H), 6.60 (s, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[C:8]([NH:10][C:11](=[O:12])[C:5]=1[CH:6]=2)=[O:9])([O-:3])=[O:2].[CH:15](Br)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:15]([N:10]1[C:11](=[O:12])[C:13]2=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]2[C:8]1=[O:9])([CH3:17])[CH3:16]
Reactant: O=C1NC(=O)c2cc1ccc2[N+](=O)[O-]
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Temperature: 60 °C
Yield: 70 %

Procedure:
4-Nitroisophthalimide (25.0 g, 130.0 mmol) was dissolved in DMF (250 mL). Isopropyl bromide (61.0 mL, 650 mmol) and potassium carbonate (36.0 g, 260 mmol) were added and the mixture was heated to 60° C. overnight. Water (1.0 L) was added, and the precipitate formed was collected by filtration, washed twice with water and dried overnight in a vacuum oven to afford 21.3 g (70%) of pure N-isopropyl-4-nitrophthalimide.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH:44]1([O:48][C:49]2[CH:50]=[C:51]([CH:55]=[C:56]([N:58]3[CH2:62][CH2:61][CH2:60][C:59]3=[O:63])[CH:57]=2)[C:52]([OH:54])=O)[CH2:47][CH2:46][CH2:45]1.[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:52](=[O:54])[C:51]1[CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=[C:49]([O:48][CH:44]2[CH2:45][CH2:46][CH2:47]2)[CH:50]=1)[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: O=C(O)c1cc(OC2CCC2)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(OC2CCC2)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3-cyclobutyloxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D46) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])(OCC)=[O:2].O.[NH2:30][NH2:31].[OH:32][S:33]([OH:36])(=[O:35])=[O:34]>C(O)C>[S:33]([OH:36])([OH:35])(=[O:34])=[O:32].[NH:30]([C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])=[O:2])[NH2:31]
Reactant: NN
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)CCC(=O)NN)[C@@H](O)[C@H]1O
Reaction time: 8 h

Procedure:
Compound 13a (115 mg, 0.29 mmol) was dissolved in 10 mL of anhydrous ethanol and hydrazine monohydrate (73 mg, 0.07 mL, 1.46 mmol) was added to the solution. The reaction mixture was heated to reflux overnight. Hydrazine monohydrate (0.07 mL) was added again and heating was continued overnight. The resulting solution was evaporated to dryness. The crude product was purified by column chromatography (4:1:0.5 chloroform:methanol:NH4OH). The desired fractions were collected, concentrated, and dried in vacuo to yield a sticky solid. The product was dissolved in 8 mL of EtOH and 2N H2SO4 was added drop wise. The salt that was precipitated out was filtered and washed with EtOH. This salt, which was hygroscopic in nature, was dissolved in water (2 mL) and lyophilized to give a white solid: yield 71 mg (65%), MS: m/z 381 (M+H)+; 1HNMR (D2O) δ 8.44 (s, 1H, H-2), 6.09 (d, 1H, H-1′, J1′,2′=5.6 Hz), 5.10 (dd, 1H, H-2′, J2′,3′=4.5 Hz), 4.53-4.62 (bm, 2H, H-3′, H-4′), 3.86-3.94 (m, 1H, 5′-CH2), 3.52-3.66 (m, 3H, 5′-CH2, N(CH3)—CH2), 2.95 (s, 3H, N—CH3), 2.86 (t, 2H, NHCO—CH2), 2.70 (s, 3H, 8-CH3); UV λmax, nm, pH 1, 258.4 (∈ 15,000), pH 7, 259.3 (∈ 15,200), pH 13, 260.4 (∈ 15,700). Anal. (C15H24N8O4.2.0H2SO4.2.7H2O) C, H, N, S.
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[N:25]=[C:22]([C:23]=1[CH3:24])[CH:21]=[C:20]1[NH:26][C:17]([C:18]([CH3:29])=[C:19]1[CH2:27][CH3:28])=[CH:16][C:15]1=[N:30][C:12]([C:13]([CH2:32][CH2:33][CH2:34][Br:35])=[C:14]1[CH3:31])=[CH:11][C:9]1[NH:10][C:6](=[C:7]([CH3:40])[C:8]=1[CH2:36][CH2:37][CH2:38]Br)[CH:5]=2)[CH3:2].[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[Br-:35].[Br-:35].[CH2:1]([C:3]1[C:4]2[N:25]=[C:22]([C:23]=1[CH3:24])[CH:21]=[C:20]1[NH:26][C:17]([C:18]([CH3:29])=[C:19]1[CH2:27][CH3:28])=[CH:16][C:15]1=[N:30][C:12]([C:13]([CH2:32][CH2:33][CH2:34][N+:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:14]1[CH3:31])=[CH:11][C:9]1[NH:10][C:6](=[C:7]([CH3:40])[C:8]=1[CH2:36][CH2:37][CH2:38][N+:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:5]=2)[CH3:2]
Reactant: CCC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(C)c5CCCBr)C(CCCBr)=C4C)c(C)c3CC
Reactant: c1ccncc1
Product: CCC1=C(C)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(C)c5CCC[n+]1ccccc1)C(CCC[n+]1ccccc1)=C4C)c(C)c3CC
Product: [Br-]
Yield: 81.1 %

Procedure:
To 100 mg of 7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis(3-bromopropyl)-21H,23H-porphin, 2 ml of pyridine is added, followed by refluxing for 5 hours. The precipitated crystals are recovered by filtration, washed with 3 ml of pyridine and dried, whereby 100 mg (yield 81.1%) of dark reddish brown desired compound is obtained.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8][C:9]1[N:13]=[C:12]([NH2:14])[NH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.O>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:11]2[C:12]([NH2:14])=[N:13][C:9]([S:8][CH3:7])=[N:10]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CSc1n[nH]c(N)n1
Solvent: C1COCCO1
Solvent: O
Solvent: c1ccncc1
Product: CSc1nc(N)n(C(=O)c2ccc(Cl)cc2)n1
Temperature: -5 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
4.7 g of pyridine are added to a solution of 7.8 g of 3-methylthio-5-amino-1H-1,2,4-triazole [Monatshefte fur Chemie 106, 1291 (1975)] in 200 ml of dioxane, then 10.8 g of 4-chloro-benzoylchloride are added dropwise at -5° C. The reaction mixture is stirred for one hour at -5° C., then for a further one hour at room temperature, finally 100 ml of water are added at water-cooling and the entire mixture is extracted with chloroform. The chloroform layer is washed with water, dried, evaporated to dryness, yielding 13.46 g (83.5 percent) of 1-(4-chloro-benzoyl)-3-methylthio-5-amino-1,2,4-triazole, m.p. 175° to 177° C. (following boiling with alcohol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si](C)(C)C#CC=C1CCNCC1.[CH2:33]([O:35][C:36]1[CH:37]=[C:38](Br)[CH:39]=[CH:40][CH:41]=1)[CH3:34].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:33]([O:35][C:36]1[CH:41]=[C:40]([C:16]#[C:15][CH:14]=[C:11]2[CH2:12][CH2:13][N:8]([C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)[CH:39]=[CH:38][CH:37]=1)[CH3:34]
Reactant: CCOc1cccc(Br)c1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CC=C1CCNCC1
Agent: [F-]
Solvent: O
Product: CCOc1cccc(C#CC=C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)c1
Yield: 46 %

Procedure:
The title Compound was prepared from Compound 274c following the procedure described for the compound of Example 274 but using 3-ethoxybromobenzene instead of 1-bromo-3,5-difluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from PE:EtAc 1:0 to 8:2 affording the title product. Yellow solid. Yield: 46%.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].[Cu:23]>>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cu+2:23].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [Cu]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: [Cu+2]

Procedure:
To the reaction flask was charged 27.64 g (0.100 mole) of oleic acid, 10.0 g of mineral spirits and 80.0 g of 0.1N sodium hydroxide. A copper rod was used as the anode and a graphite rod as the cathode. 6,496 coulombs of electricity were passed and 2.30 g (0.030 mole) of copper was consumed. After isolation of the product, a green solution of copper oleate in mineral spirits containing 6% copper was obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[BH3-][C:12]#[N:13].[Na+].[CH3:15]COC(C)=O.C([O-])(O)=O.[Na+]>CC#N.C=O.O.C(O)(=O)C>[Br:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([N:13]([CH3:12])[CH3:15])[CH:9]=1)[C:5]#[N:6]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc(N)cc(Br)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)c1cc(Br)cc(C#N)c1
Reaction time: 0.67 h
Yield: 28 %

Procedure:
To a stirring suspension of 210 mg (10.6 mmol) of 3-amino-5-bromobenzonitrile in 11 mL of CH3CN and 11 mL of 37% formaldehyde in H2O was added 222 mg (3.53 mmol) of NaCNBH3 followed by about 7 drops of acetic acid to a pH=7. After 1 h 40 min., an additional amount of acetic acid (10 drops) was added. After 15 h, 40 mL of EtOAc and 40 mL of sat. NaHCO3 was added, and the layers were separated. The organic layer was washed with 25 mL of sat. NaHCO3 and 25 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 67.4 mg of 3-bromo-5-(dimethylamino)benzonitrile as a yellow solid in 28% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].CC[N:15](C(C)C)[CH:16]([CH3:18])[CH3:17].CC(N)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:15][CH:16]([CH3:18])[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1nc2ccncc2nc1Cl
Solvent: CC(C)N
Solvent: ClCCl
Product: CC(C)Nc1nc2ccncc2nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 2,3-dichloropyrido[3,4-b]pyrazine (2.5 g, 12.50 mmol) and DIPEA (6.53 mL, 37.5 mmol) in DCM (25 mL) was added propan-2-amine (1.065 mL, 12.50 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, warmed slowly to 23° C., and stirred for 12 h. The crude mixture was partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl (100 mL). The layers were separated and the aqueous phase was washed with EtOAc (4×100 mL). The organic extracts were combined, washed with brine (50 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo. The crude material was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a gradient eluant of 50% to 75% EtOAc in heptane on a 80 g silica gel column (Single Step™) to give the title compound (1.828 g, 65.7%) as a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.6 Hz, 6H), 4.39-4.49 (m, 1H), 7.49 (dd, J=5.8, 0.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.95 (d, J=0.8 Hz, 1H); ESI-MS m/z [M+H]+ 223.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](CC([Cl:13])=O)=[CH:6][CH:5]=1)([O-])=O.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl.[CH3:28][CH2:29][O:30][CH2:31][CH3:32]>C(Cl)(Cl)Cl>[ClH:13].[N:1]1([C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]2[CH:23]([C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=2)[C:24]([OH:26])=[O:25])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOCC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)C(c1ccc([N+](=O)[O-])cc1)[C@@H]1CCCC[C@H]1N1CCOCC1

Procedure:
4-Nitrophenylacetyl chloride, prepared according to the method described in Example 8 using 4-nitrophenylacetic acid (5.4 g, 29.8 mmol), is dissolved in chloroform (15 mL). This solution is refluxed for 9 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (5.25 g, 28.3 mmol) in chloroform (15 mL) under nitrogen. The solvent is removed in vacuo, and the residue is partitioned between 1M hydrochloric acid (60 mL) and ether (50 mL). The ether layer is separated and the aqueous layer is washed with more ether (2×50 mL), and then basified by the addition of 50% sodium hydroxide solution. This is then extracted with ether (5×60 mL), and the combined ether extracts are washed repeatedly with water to remove any unreacted aminoalcohol. The ether containing the product is then dried over sodium sulfate, and the solvent is removed to leave the crude free ester. The residue is dissolved in ether (20 mL) and treated with HCl in ether to precipitate the salt. It is washed with ether and recrystallised from hot methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].O.CO>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cc(Cl)cc1Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCc1c(F)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-6-fluorobenzonitrile (3.87 mmol) in 15 mL THF was added a solution of BH3 (15.5 mmol, 1M in THF) and the mixture was stirred at 60° C. for 1 h. After cooling to 0° C., water was added followed by MeOH and the mixture was then heated to 70° C. for 10 min. The solvent was evaporated, the residue was taken up in water and EtOAc. The aqueous phase was separated, basified with 1M NaOH and it was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired product as yellow oil.