Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (5.00 g, supplier Aldrich) in DCM (200 ml) was added DIPEA (9.85 ml) and then 4-(trifluoromethyl)benzenesulfonyl chloride (7.22 g, supplier Aldrich). The reaction mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then reduced to dryness in vacuo, to give 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:43])([F:42])[C:20]([F:41])([F:40])[C:21]([F:39])([F:38])[O:22][C:23]([F:37])([C:28]([F:36])([F:35])[O:29][C:30]([F:34])=[C:31]([F:33])[F:32])[C:24]([F:27])([F:26])[F:25]>C1COCC1>[F:33][C:31]([F:32])([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH:30]([F:34])[O:29][C:28]([F:35])([F:36])[C:23]([F:37])([O:22][C:21]([F:38])([F:39])[C:20]([F:40])([F:41])[C:19]([F:18])([F:42])[F:43])[C:24]([F:27])([F:26])[F:25]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
In the dry box, THF (500 mL) and methyl 4-hydroxybenzoate (26.6 g, 0.175 mol) were added to an oven dry RB flask equipped with a stirrer, Potassium carbonate (12.00 g, 0.087 mol) was then added. 1,1,1,2,2,3,3-Heptafluoro-3-(1,1,1,2,3,3-hexafluoro-3-(1,2,2-trifluorovinyloxy)propan-2-yloxy)propane (94.5 g, 0.219 mol) was then added via the addition funnel and the reaction allowed to stir at room temperature. The reaction mixture was heated to a gentle reflux, oil temperature about 80° C., under nitrogen overnight. An aliquot was withdrawn and concentrated under vacuum and analyzed via proton NMR that showed the complete conversion to the desired material. The cooled reaction mixture was then filtered through silica gel and then concentrated at reduced pressure, resulting in 101.52 g (99.33%) yield of the desired material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.II.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([C:11]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:17])[CH2:18][CH2:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)([OH:21])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(CCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Yield: 30.8 %

Procedure:
To a stirred suspension of (S)-tert-butyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (13 g, 28.9 mmol) and zinc powder (9.4 g, 0.144 mol) in THF (200 mL) at rt was added iodine (4.40 g, 0.173 mol) and ethyl bromoacetate (9.7 g, 57.7 mmol). The mixture was heated at reflux for 2 h, and quenched by addition of water. The mixture was filtered through a celite pad, the filtrate was extracted with EtOAc. The organic phase was concentrated to give the crude product, which was purified by column chromatography to afford ethyl 5-(((S)-1-(4-bromophenyl)ethyl)(tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)-3-hydroxypentanoate (4.8 g, 31%). 1H NMR (CDCl3): δ 1.02 (t, 3H), 1.29-1.41 (m, 12H), 1.88 (m, 1H), 2.51-2.73 (m, 3H), 2.99 (m, 1H), 3.96 (q, 2H), 4.03 (m, 1H), 4.36 (m, 1H), 4.77 (m, 1H), 5.33 (m, 1H), 6.88-6.96 (m, 4H), 7.11 (m, 2H), 7.24 (m, 1H), 7.36 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=2[F:17])=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Br)cnn1C
Yield: 72.6 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.027 g, 0.095 mmol) was treated with 2,4-difluorophenyl isocyanate (0.015 g, 11.5 μL, 0.095 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 8 (0.030 g, 0.069 mmol, 71%) as a white solid. LCMS m/z (%)=437 (M+H79Br, 100), 439 (M+H81Br, 91). 1H NMR (400 MHz, acetone-d6) δ: 8.45 (s, 1H), 8.23 (dt, J=6.1, 9.2 Hz, 1H), 7.93 (s, 1H), 7.68 (dd, J=2.6, 9.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.14 (d, J=9.0 Hz, 1H), 7.07 (ddd, J=2.7, 8.7, 11.3 Hz, 1H), 6.93-7.02 (m, 1H), 3.82 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [CH2:1]([O:3]/C(=C\C1C=CC(C2C=CC=C(N(C)C(NC3C=CC(C(F)(F)F)=CC=3)=O)C=2)=CC=1)/C(OCC)=O)[CH3:2].C(O/[C:41](=[CH:45]\[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N:58]([CH3:72])[C:59]([NH:61][C:62]3[CH:67]=[CH:66][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:64][CH:63]=3)=[O:60])[CH:53]=2)=[CH:48][CH:47]=1)/[C:42]([OH:44])=[O:43])C>>[CH3:2][CH2:1][O:3]/[C:45](/[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N:58]([CH3:72])[C:59]([NH:61][C:62]3[CH:63]=[CH:64][C:65]([C:68]([F:70])([F:69])[F:71])=[CH:66][CH:67]=3)=[O:60])[CH:53]=2)=[CH:48][CH:47]=1)=[CH:41]\[C:42]([OH:44])=[O:43]
Reactant: CCO/C(=C\c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1)C(=O)O
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1)OCC
Product: CCO/C(=C\C(=O)O)c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 43e, starting with 1.5 g (3 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[1-methyl-3-(4-trifluoromethylphenyl)ureido]biphenyl-4-yl}acrylate, g (%) of (Z)-2-ethoxy-3-{3′-[1-methyl-3-(4-trifluoromethylphenyl)ureido]biphenyl-4-yl}acrylic acid are obtained in the form of a tacky paste.
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH2:17])[N:11]=1.[Cl-].[NH4+]>ClCCl>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:1][CH2:17]2)[N:11]=1
Reactant: CC[Zn]CC
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc(Br)n1
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(c2cccc(Br)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of diethylzinc (1M in hexane, 2.0 mL, 2.0 mmol) in dichloromethane (3.7 mL) at −4° C. was added chloroiodomethane (714 mg, 4.0 mmol) dissolved in dichloromethane (1 mL) dropwise. The reaction mixture was stirred at 0° C. for 15 minutes. A solution 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)vinyl)pyridine (200 mg, 0.6 mmol) in dichloromethane (3.0 mL) was added. The reaction mixture was stirred at 0° C. for 2 h. A cold saturated aqueous solution of ammonium chloride was added and the mixture was extracted with dichloromethane. The organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via flash chromatography (100% heptanes) to afford 2-bromo-6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)pyridine (120 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H), 1.22-1.28 (m, 2H), 1.39-1.45 (m, 2H), 7.23 (dd, 1H), 7.47 (t, 1H), 7.60 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34](=[O:50])[N:35]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:36]2=[O:41]>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:35]2[C:34](=[O:50])[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[CH2:31][NH:30][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:9])[C:36]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cn1cncc1C(=O)O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cncc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (0.3 g, 2.6 mmol) and carbonyl diimidazole (0.5 g, 3.0 mmol) in DMF (30 mL) was stirred at room temperature for 3 hours. Triethylamine (0.8 g, 6.0 mmol) was added, followed by 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol). The mixture was stirred at 75° C. (oil bath) for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 3-methyl-3H-imidazole-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.2 g. 28%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.50-2.64 (m, 2H), 2.84-2.97 (m, 1H), 3.81 (s, 3H), 4.89 (d, J=5.6 Hz, 2H), 5.13-5.20 (dd, J=5.2 and 12.5 Hz, 1H), 7.68-7.84 (m, 5H), 8.94 (t, J=5.5 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.98, 30.93, 33.51, 37.44, 48.88, 121.88, 125.45, 127.05, 131.52, 132.29, 133.09, 134.83, 139.42, 142.08, 160.25, 166.94, 167.53, 169.82, 172.74; Anal. calcd. for C19H17N5O5+0.13H2O+0.1Et2O: C, 57.52; H, 4.54; N, 17.29. Found: C, 57.23; H, 4.27; N, 16.95.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:35]3[CH2:36][CH2:37][CH:32]([C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=4)[CH2:33][CH2:34]3)=[O:16])=[CH:19][CH:20]=2)[CH:2]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Agent: Cl
Product: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(-n4cnc5cccnc54)cc3)CC2)cc1
Yield: 66.6 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and (4-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (287 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (329 mg) was obtained.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].O>C1COCC1>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:46]([CH3:49])[CH:47]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=2)=[CH:43][CH:44]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(C)Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
A solution of (4-methoxyphenyl)methyltriphenylphosphonium bromide (2.40 g, 5.18 mmol, 1.0 equiv.) in THF (10 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 3.2 mL, 5.18 mmol, 1.0 equiv.) at 0° C., the red suspension was stirred at 0° C. for 15 min. 3-(4-tert-Butylphenyl)-2-methylpropanal (1.59 g, 7.77 mmol, 1.5 equiv.) in THF (4 mL) was added, and the mixture was stirred at 0° C.→25° C. for 12 h. After addition of H2O at 25° C., the aqueous layer was extracted with hexanes, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5→99:1) to yield 1.33 g (83%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:11]=1.[CH3:21][O:22][C:23]1[C:26](=O)[C:25](=[O:28])[C:24]=1[O:29]C>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:26]2[C:25](=[O:28])[C:24](=[O:29])[C:23]=2[O:22][CH3:21])[N:11]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Solvent: CO
Product: COc1c(NCCCCCc2csc(NC(N)=NCC(F)(F)F)n2)c(=O)c1=O
Yield: 40.6 %

Procedure:
To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.4 g.) in methanol (1.5 ml.) was added 1,2-dimethoxycyclobutene-3,4-dione (0.2 g.). After 2.5 hours at room temperature the mixture was evaporated to dryness, and the residue purified by preparative thin layer chromatography using methanol/chloroform 1:9 v/v as developing solvent. The appropriate band was isolated to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-methoxycyclobutene-3,4-dione (0.22 g.) which was dissolved in propargylamine (1 g.) and the mixture allowed to stand at room temperature overnight. The mixture was then evaporated to dryness, and the residue purified by preparative thin layer chromatography using chloroform/methanol/aqueous ammonia 90:10:1 v/v/v as developing solvent. The product from this purification was treated in methanol/acetone with excess maleic acid and the resulting salt precipitated by the addition of diethyl ether to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]-thiazol-4-yl)pentylamino]-2-propargylaminocyclobutene-3,4-dione hydrogen maleate. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ):-1.5 (multiplet, 6H); 3.3 (singlet, 1H); 3.5 (multiplet, 2H); 4.1 (quartet, 2H); 4.8 (quartet, 2H); 6.6 (singlet, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CC(=O)CC>[CH3:21][O:20][C:18](=[O:19])[CH2:17][O:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1ccc(C)c(C)c1

Procedure:
A mixture of 3,4-dimethyl-phenol (5.000 g; 40.928 mmol), potassium carbonate (7.070 g; 51.160 mmol), and methyl bromoacetate (4.70 ml; 51.160 mmol) in butanone (280 ml) was heated at reflux for 4 h. Filtration, concentration to dryness under reduced pressure, and purification by FC (heptane/EA, 4/1) afforded (3,4-dimethyl-phenoxy)-acetic acid methyl ester as a pale yellow oil (7.400 g; 93%). LC-MS: tR=0.92 min.; [M+H]+: no ionisation.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=2N)=[N:2]1.N(OCCCC)=O.[CH3:21][S:22]C>[Cu]Cl>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:7]([S:22][CH3:21])[C:6]=1[C:3]1[CH2:4][CH2:5][O:1][N:2]=1
Reactant: CSC
Reactant: Cc1cccc(N)c1C1=NOCC1
Agent: Cl[Cu]
Agent: CCCCON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
40 g (0.22 mol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline and 0.44 g of copper(I) chloride are initially charged in 300 ml of dimethyl sulfide, and 26.1 g of n-butyl nitrite (0.23 mol) are added dropwise at 55-66° C. The mixture is then stirred at 60° C. for 1.5 hours. For work-up, the mixture is then washed with dilute hydrochloric acid and water and then concentrated under reduced pressure. This gives 38.7 g (85%) of a dark oil which solidifies after a while (content according to HPLC 94%). The product can be purified further by trituration in methyl tert-butyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(Br)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A 100 mL round-bottom flask was charged with 4-bromo-2-methoxybenzaldehyde (1.90 g, 8.84 mmol, 1.10 equiv), tert-butyl piperazine-1-carboxylate (1.50 g, 8.05 mmol, 1.00 equiv), and dichloromethane (30 mL). The resulting solution was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (5.10 g, 24.0 mmol, 3.00 equiv) was added. The resulting solution was stirred for overnight at room temperature and then diluted with water (30 mL). The resulting mixture was extracted with dichloromethane (2×20 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 2.66 g (86% yield) of tert-butyl 4-[(4-bromo-2-methoxyphenyl)methyl]piperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 385 [M+H]+.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[NH:1]([C:31]([O:33][CH2:34][CH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]2[C:47]1=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:32])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[F:48][C:49]([C:50]([OH:52])=[O:51])([F:54])[F:53]
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCCCNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fmoc-Phe-Gly-NH—(CH2)6NH-Boc (0.7 g) was dissolved in CH2Cl2 (4 mL) at 0° C. under N2 and then trifluoroacetic acid (TFA) (4 mL) was added. The reaction mixture was allowed to warm to RT and stirred for 2 hours under N2. The solvents were removed under reduced pressure and the residue dried at high vacuum to provide 0.71 g of Fmoc-Phe-Gly-NH(CH2)6—NH2.TFA. This crude material was used to prepare without further purification.
Reaction SMILES: C1O[C:4]([CH2:6][CH2:7][CH2:8]Cl)([CH3:5])[O:3]C1.[N-:11]=[N+:12]=[N-:13].[Li+]>CN(C=O)C>[N:11]([CH2:8][CH2:7][CH2:6][C:4](=[O:3])[CH3:5])=[N+:12]=[N-:13]
Reactant: CC1(CCCCl)OCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(=O)CCCN=[N+]=[N-]
Reaction time: 24 h

Procedure:
5-Chloro-2-pentanone ethylene ketal (5.0 g, 30.4 mmol) was stirred in DMF with lithium azide (5.95 g, 120 mmol) at 60° C. for 48 hrs. The mixture was evaporated to dryness. The product was then dissolved in toluene (50 ml) and washed with water (3×15 ml). The organic phase was evaporated and the resulting 5-azido-2-pentanone ethylene ketal was stirred in 50 ml of 70% trifluoroacetic acid for 24 hrs. The reaction mixture was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated to yield the desired ketone as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:18][S:19][CH3:20])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].CC(C)([O-])C.[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C=O)C>[CH3:17][O:16][C:15]1[CH:14]=[CH:13][C:4]([C:5]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6])=[C:3]([CH2:18][S:19][CH3:20])[C:2]=1[NH:1][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCOC(=O)c1ccc(OC)c(N)c1CSC
Reactant: CCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCNc1c(OC)ccc(C(=O)OCCCCC)c1CSC
Temperature: 100 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
Pentyl 3-amino-4-methoxy-2-methylthiomethylbenzoate (830 mg, 2.79 mmol) and DMF (4.0 ml) were mixed, and potassium t-butoxide (470 mg, 4.19 mmol) and bromopentane (0.62 ml, 5.0 mmol) were successively added to this solution. The mixture was stirred at 100° C. for 1 hour and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=15/1) to give pentyl 4methoxy-2-methylthiomethyl-3-pentylaminobenzoate (178 mg, 17%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:4][C:5](NC(=O)OC(C)(C)C)=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[BrH:25].N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Br:25][C:5]1[CH:4]=[C:3]([O:21][CH:22]([CH3:24])[CH3:23])[C:2]([Cl:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][NH:9][C:10]2=[O:12]
Reactant: CC(C)Oc1cc(NC(=O)OC(C)(C)C)c2c(c1Cl)C(=O)NCC2
Reactant: Br
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Br)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 209.3 %

Procedure:
To a solution of tert-butyl [8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]carbamate (77c, 500 mg, 0.282 mmol) in THF (20 mL) was added HBr (10.0 mL, 88.4 mmol, 48% aqueous solution). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0° C., CuBr (303 mg, 2.11 mmol) was added, followed by addition of NaNO2 (1.07 mL, 1.55 mmol, 100 mg/mL solution). The resulting reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was neutralized with NaHCO3 and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (1×100 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-100% EtOAc/heptanes) to give 5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77d, 188 mg, 42% over two steps) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([CH3:16])[C:13](O)=[S:14])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([CH3:16])[C:13]([Cl:19])=[S:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CSCC(C)C(O)=S)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(CSCC(C)C(=S)Cl)cc1

Procedure:
3-[[(4-Methoxy)phenylmethyl]thio]-2-methylthiopropanoic acid prepared according to the procedure of Example 10 in U.S. Pat. No. 4,116,962 is treated with thionyl chloride to yield 3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloride.