Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][OH:17])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:27]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][O:17][CH3:27])[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (150 mg) in THF (3 mL) was added sodium hydride (24 mg), and the mixture was stirred at room temperature for 15 min. To this solution was added methyl iodide (85 mg), and the mixture was stirred for 2 hr. Furthermore, sodium hydride (24 mg) was added, and the mixture was stirred at room temperature for 4 hr. To the reaction solution was added ice water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (151 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[O:25][C:26]=1[CH3:27])[CH3:2]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O.C1COCC1.[Cl:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:24](/[CH:23]=[CH:22]/[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)(=[O:25])=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=S(=O)(Cl)/C=C/c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(/C=C/c1cccc(Cl)c1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.7 %

Procedure:
To a well-stirred solution of 3-chloroaniline (367.9 mg, 2.87 mmol, 1 eq.) in a solvent system of H2O-THF (14 mL, 1:1 ratio) was sequentially added first compound 1 (676.6 mg, 2.87 mmol, 1 eq.) and then a 1M-solution of Na2CO3 (2.2 mL, 0.77 mmol, 0.77 eq.) until the pH was about 8. After the reaction mixture was stirred for 22 hours at room temperature, water was added and the product was extracted 3 times with EtOAc from the aqueous phase. The resulting organic phase was washed with brine, dried under Na2SO4 and the solvent evaporated. After the product was purified from the crude by flash column chromatography (10% EtOAc/hexanes), compound 2 (808.5 mg, 2.46 mmol) was obtained in an 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=15.4 Hz, C═CH, 1H), 7.43 (s, ArH, 1H), 7.39 (dt, J=6.8, 2.3 Hz, ArH, 1H), 7.33 (m, ArH, 2H), 7.25 (t, J=8.0, ArH, 1H), 7.22 (t, J=2.1, ArH, 1H), 7.13 (ddd, J=8.0, 1.9, 0.9 Hz, ArH, 1H), 7.07 (ddd, J=8.0, 2.1, 0.9 Hz, ArH, 1H), 6.79 (d, J=15.4 Hz, C═CH, 1H), 6.61 (s, NH, 1H). 13C NMR (100 MHz, CDCl3, δ): 142.03 (CH), 137.53 (C), 135.17 (C), 133.76 (C), 131.14 (CH), 130.55 (CH), 130.36 (CH), 128.11 (CH), 126.67 (CH), 125.38 (CH), 125.30 (CH), 120.49 (CH), 118.46 (CH). GC-MS m/z (% relative intensity, ion): 330.85 (0.8, M+4), 328.95 (4, M+2), 326.90 (6, M+), 262.95 (28), 151.95 (48), 136.95 (99), 126.95 (54), 102.00 (100), 98.80 (51), 90.95 (19).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH3:31])[C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[N:18]=[CH:17][N:16]=2)=[O:13])[CH2:7][CH2:6]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][C:12](=[O:13])[N:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:32])[CH2:6][CH2:7]3)[CH3:31])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3)ncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ncn2)CC1
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 99.9 %

Procedure:
After adding 20% palladium hydroxide-carbon (51.8 mg) to a solution of 1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methyl-3-[6-(4-nitrophenoxy)pyrimidin-4-yl]urea (131 mg) in tetrahydrofuran (10.0 ml), the mixture was stirred for 10.5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and the then washed with methanol. The filtrate was concentrated to provide a crude product of the title compound (122 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.ClCCl>[NH2:1][C:2]1[C:7]([Br:20])=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Nc1ccc(-c2ccc(F)cc2)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ncc(-c2ccc(F)cc2)cc1Br
Yield: 105.7 %

Procedure:
To a solution of 2-amino-5-(4-fluorophenyl)pyridine (0.80 g, 4.25 mmol) in 20 ml glacial acetic acid was added sodium acetate (1.39 g, 17.0 mmol). Subsequently, a solution of bromine (0.44 mL, 8.50 mmol) in 2 ml glacial acetic acid was added dropwise to the reaction by addition funnel. After the addition, the reaction was heated to reflux for 1 hour then cooled and diluted with dichloromethane. The solution was washed with 25 ml saturated aqueous sodium hydrogen sulfate and then 25 ml water then dried over magnesium sulfate and concentrated to a brown oil. Automated purification on a silica gel ISCO column (120 g column, 2.5% MeOH—CH2Cl2) gave 1.20 g (60%) of 2-amino-3-bromo-5-(4-fluorophenyl)pyridine as an off-white/pink solid.
Reaction SMILES: Br[C:2]1[C:3]([O:37][CH3:38])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1.CC(C)([O-])C.[Na+].C(=[NH:58])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:36][C:32]1[CH:31]=[C:30]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH2:58])[C:3]=3[O:37][CH3:38])[N:7]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:6]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1c(Br)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1c(N)ccc2c1c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A total of 810 mg of 5-bromo-3-(3-fluoro-phenyl)-4-methoxy-1-trityl-1H-indazole obtained in Production Example II-18-a was dissolved in 7.2 ml of toluene, 194 mg of sodium t-butoxide, 0.29 ml of benzophenoneimine, 135 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 74.5 mg of tris(dibenzylideneacetone)bispalladium were added, and the mixture was stirred at 80° C. in an atmosphere of nitrogen gas for 8 hours. The reaction mixture was cooled to room temperature, and diethyl ether was added. The mixture was filtrated through Celite, and the filtrate was evaporated. The resulting residue was dissolved in 7.2 ml of tetrahydrofuran and 0.36 ml of 2 N hydrochloric acid was added, followed by stirring at room temperature for 3 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:3), to give 426 mg of the title compound as reddish brown crystals.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:55])=[N:33][C:34]=2[NH:38][CH2:39][CH:40]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:48]([CH:40]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:39][NH:38][C:34]1[N:33]=[C:32]([I:55])[N:31]=[C:30]2[C:35]=1[N:36]=[CH:37][N:29]2[C@@H:11]1[O:12][C@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(Cc4ccccc4)Cc4ccccc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(Cc4ccccc4)Cc4ccccc4)nc(I)nc32)[C@H](O)[C@@H]1O
Yield: 85.4 %

Procedure:
A solution of (2R,3R,4S,5S)-4-(benzoyloxy)-2-{6-[(2-benzyl-3-phenylpropyl)amino)-2-iodo-9H-purin-9-yl}-5-[(ethylamino)carbonyl]tetrahydro-3-furanyl benzoate (Preparation 20) (0.26 g, 0.31 mmol) and sodium carbonate (33 mg, 0.3 mmol) in methanol (5 ml) was stirred at room temperature for 14 hours. Solvent was removed under reduced pressure and the residue dissolved in dichloromethane:methanol (99:1 by volume; 5 ml) and filtered. Solvent was again evaporated under reduced pressure and the residue triturated with diethyl ether to afford the title compound as a beige powder (0.17 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCCCC1.[Br:20]N1C(=O)CCC1=O>C(OC(=O)C)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][Br:20])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)OC(C)(C)C)s1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)c1ccc(CBr)s1
Yield: 98.6 %

Procedure:
To 5-Methyl-thiophene-2-carboxylic acid tert-butyl ester (10.8 g, 54.5 mmol) was added cyclohexan (100 mL) and N-bromosuccinimide (9.7 g, 54.5 mmol) and was heated at reflux overnight. The suspension was to added ethylacetate (200 mL) and the organic solution was washed with water (4×100 mL). The solvent was removed in vacuo to yield 14.9 g of 5-bromomethylthiophene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[C:11]([F:20])[CH:10]=1)=[O:7].[H][H]>O1CCCC1.CO.[C].[Pd]>[CH3:27][Si:24]([CH3:25])([CH3:26])[C:22]1[CH:21]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:29])([CH3:28])[CH3:1])[CH:23]=1)[C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:11]([F:20])[CH:10]=1)=[O:7]
Reactant: C[Si](C)(C)c1cc(C(=O)Nc2ccc(C=CC(=O)O)c(F)c2)cc([Si](C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(=O)Nc2ccc(CCC(=O)O)c(F)c2)cc([Si](C)(C)C)c1
Yield: 75.9 %

Procedure:
Compound 2 (160 mg) was dissolved in a mixed solution of tetrahydrofuran (0.59 ml) and methanol (0.59 ml). Palladium carbon (4.4 mg) was added thereto, and the mixture was stirred in a hydrogen atmosphere for 4.5 hours. After the reaction was over, the reaction mixture was filtered through Celite. The filtrate was condensed and recrystallized with dichloromethane and n-hexane to obtain Compound 7 (122 mg, 76%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH:13]=[CH:14][CH:15]([CH3:22])[CH2:16][CH:17]=[CH:18][CH:19]([CH3:21])[CH3:20])[CH2:3][O:4]CC1C=CC=CC=1.[H][H]>C(OCC)(=O)C>[CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][OH:4]
Reactant: CC(C)C=CCC(C)C=CCC(C)COCc1ccccc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CC(C)CCCC(C)CCCC(C)CO
Reaction time: 5 h
Yield: 85.8 %

Procedure:
A mixture of 0.15 g (0.5 mmole) of rac. benzyl 2,6,10-trimethylundeca-4,8-dien-1yl ether, 0.1 g of 5% by weight palladiumon 95% by weight carbon and 10 ml. of ethyl acetate was stirred in an atmosphere of hydrogen for 16 hours at room temperature. The catalyst was filtered and the filtrate was concentrated in vacuo. The oily residue was dissolved in 10 ml. of ethyl acetate and rehydrogenated over 0.1 g of 5% palladium on carbon, for 5 hours at room temperature. The catalyst was again filtered and the filtrate was concentrated in vacuo. The residue wasevaporatively distilled giving 0.092 g (86%) of rac. 2,6,10-trimethylundecan-1-ol as a colorless oil, b.p. 100°-105° C. (bath temperature) (0.02 mm Hg.).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH2:52][N:51]([CH3:56])[CH2:50][CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:47]=[C:48]3[C:53](=[CH:54][CH:55]=2)[CH2:52][N:51]([CH3:56])[CH2:50][CH2:49]3)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCc2cc(Nc3nc(Br)cn(C)c3=O)ccc2C1
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 58 %

Procedure:
Following Example 148b, 290 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 209 mg 5-bromo-1-methyl-3-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyrazin-2(1H)-one 221b were reacted to give 283a as a yellow solid (217 mg, 58%). MS: [M+H]+ 699
Reaction SMILES: Br.C(O[CH2:6][CH2:7][N:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]1=[NH:18])(=O)C.P(Br)(Br)([Br:21])=O.C(#N)CC.C(=O)(O)[O-].[Na+]>>[Br:21][C:6]1[N:18]=[C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][N:8]2[CH:7]=1
Reactant: CC(=O)OCCn1cc(C(F)(F)F)ccc1=N
Reactant: O=P(Br)(Br)Br
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: FC(F)(F)c1ccc2nc(Br)cn2c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 61.6 %

Procedure:
A mixture of 1.63 g of (2-imino-5-trifluoromethyl-2H-pyridin-1-yl)ethyl acetate hydrobromide, 2.84 g of phosphorus oxybromide and 2 ml of propionitrile was stirred at 100° C. for 2.5 hours. The cooled reaction mixture was neutralized in a saturated aqueous sodium bicarbonate solution and a 5 M aqueous sodium hydroxide solution, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane to obtain 808 mg of 2-bromo-6-trifluoromethyl-imidazo[1,2-a]pyridine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:42])[C@@H:18]([CH2:27][C:28]1[CH:33]=[CH:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH:29]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1(C)C=CC=CC=1>[CH3:15][O:16][C:17](=[O:42])[C@@H:18]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:32][CH:33]=1)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21]
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)[C@@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccc(-c2ccsc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of N-t-butoxycarbonyl-D-tyrosine methyl ester (2.5 g, 9.48 mmol) in 10 mL of methylene chloride and pyridine (1.9 mL, 23.7 mmol) at -15° C. is added triflic anhydride (1.9 mL, 11.4 mmol). The reaction is stirred 30 minutes. The mixture is washed with water, 0.5 N NaOH, 15% aqueous citric acid, brine dried over MgSO4, filtered and concentrated giving N-t-butoxycarbonyl-4-trifluoromethanesulfonyloxy-D-phenyl alanine methyl ester. A solution of 3-thiopheneboronic acid (1.4 g, 10.9 mmol), potassium carbonate (1.13 g, 8.2 mmol) in 25 mL of toluene is heated to 80° C. and the catalyst tetrakis (triphenyl phosphine)-Pd (0.19 g, 0.16 mmol) is added. N-t-Butoxycarbonyl-4-trifluoro methanesulfonyloxy-D-phenylalanine methyl ester (2.34 g, 5.47 mmol) in 25 mL of toluene is added dropwise and stirred at 80° C. for 3 hours. The mixture is filtered through Celite and washed with ethyl acetate. The organic layer is washed with 0.5 N NaOH (2×), 15% citric acid, water, brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel with ethyl acetate/toluene (1:5) gives N-t-butoxy carbonyl-4-(3-thienyl)-D-phenylalanine methyl ester. Treatment of the above with dilute HCl in 1,4-dioxane at room temperature overnight yields 4-(3-thienyl)-D-phenylalanine methyl ester hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][CH2:22][CH2:23]OS(C)(=O)=O)=[CH:18][CH:19]=2)[C:14]([CH3:30])([CH3:29])[O:13]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>O1CCOCC1.CCOC(C)=O>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:23][CH2:22][CH2:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:12](=[C:5]1[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]1=[O:11])[O:13][C:14]2([CH3:29])[CH3:30])[CH3:32]
Reactant: CCNCC
Reactant: CC1(C)OC(=C2C(=O)Nc3ccc(F)cc32)c2ccc(CCCOS(C)(=O)=O)cc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CC)CCCc1ccc2c(c1)C(C)(C)OC2=C1C(=O)Nc2ccc(F)cc21
Yield: 55.2 %

Procedure:
A solution of methanesulfonic acid 3-[1-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene)-3,3-dimethyl-1,3-dihydro-isobenzofuran-5-yl]-propyl ester (170 mg, 0.39 mmol) and diethylamine (0.30 ml, 2.92 mmol) in dioxane (1.6 ml) was heated at 75° C. in a pressure tube for 36 hours. The mixture was evaporated, dissolved in EtOAc, and the EtOAc washed with H2O and brine. The aqueous layer was also extracted with CHCl3. The organic layers were combined, dried over anhydrous Na2SO4, and then evaporated to a yellow film. The sample was passed through a plug of silica gel eluting with 10% methanol in CHCl3 to give a yellow-orange solid. The solid was dissolved in EtOAc, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and evaporated to a yellow solid. The solid was chromatographed eluting with CHCl3/MeOH to give the title compound as a yellow solid (88 mg, 54%).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Br:9][C:10]1[CH:11]=[C:12]([CH2:16][CH:17]([CH3:22])[CH2:18][C:19]([OH:21])=O)[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[C:19](=[O:21])[CH2:18][CH:17]([CH3:22])[CH2:16]2
Reactant: CC(CC(=O)O)Cc1cccc(Br)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1CC(=O)c2ccc(Br)cc2C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with trifluoromethane sulfonic acid (450 g, 3 mol) and cooled to 0° C. with an ice-water bath. 4-(3-bromophenyl)-3-methylbutanoic acid, prepared in a similar manner as described in Example 32 (15.5 g, 60 mmol), was added as a solution in DCM (30 mL) slowly to produce a clear dark brown solution. After 15 min, the reaction was diluted with 500 mL of CHCl3 and poured slowly onto approximately 1 L of crushed ice. The resulting slurry was allowed to stir until the solution warms to room temperature and became biphasic. Following separation of layers, the aqueous layer was extracted with CHCl3. The combined organics were washed with brine and dried over anhydrous MgSO4 prior to concentration in vacuo. Purification via Isco column chromatography (50% DCM/hex isocratic) provided a quantitative yield of the named compound as a pale yellow amorphous solid. LCMS-ESI+ (m/z): [M]+ calcd for C11H11BrO: 239.11; found: 239.20.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=2)=[C:4]([CH3:31])[CH:3]=1.[C:32]([NH:35][NH2:36])(=O)[CH3:33].O=P(Cl)(Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]3[O:30][C:32]([CH3:33])=[N:35][N:36]=3)=[CH:24][CH:25]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: CC(=O)NN
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Oc3ccc(/C=C/c4nnc(C)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 100 °C
Yield: 76.5 %

Procedure:
To a 30 mL vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (100 mg, 0.230 mmol) and acetohydrazide (85 mg, 1.151 mmol) were dissolved in POCl3 (2 mL, 21.46 mmol) and the mixture was heated to 100° C. for 18 h. The reaction mixture was cooled to room temperature poured into ice. The solution was quenched with sat. sodium bicarb and diluted with DCM. The organic layer was collected (phase separator) and concentrated to provide the crude material. The crude product was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 30-100% CH3CN/H2O) to afford (E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole (83 mg, 0.176 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=2.38 (s, 3H), 2.57 (s, 3H), 3.90 (s, 3H), 6.81-6.98 (m, 4H), 6.98-7.08 (m, 2H), 7.28-7.42 (m, 2H), 7.44-7.58 (m, 4H). LC/MS (m/z, MH+): 473.4.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].O.[CH2:14](Cl)/[CH:15]=[C:16](\[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])/[CH3:17]>CO>[CH3:17]/[C:16](/[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:15]/[CH2:14][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CC(C)=CCC/C(C)=C\CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)=CCC/C(C)=C\CSc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-mercaptobenzimidazole (5.1 g, 34 mmol) and 2N NaOH/H2O (pH 11) in methanol (100 mL) was added neryl chloride (5.85 g, 34 mmol). The reaction mixture was stirred at ambient temperature for 16 hours, evaporated in vacuo, dissolved in CH2Cl2, washed with saturated NaHCO3 and brine, and dried over Na2SO4. Evaporation of the solvent gave an oil which was flash chromatographed (Merck Kieselgel, 5% MeOH/CH2Cl2) to give the title compound which was crystallized from Et2O/pentane to give a white solid (3.4 g, 35%). m.p. 98°-101° C. NMR (CDCl3)δ7.35(m 4H) 5.25(m 2H) 4.0(d,J=6 Hz,2H), 2.05(m,4H), 1.68(s,3H), 1.62(s,3H), 1.60(s,3H).