Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH2:13][CH3:14])[CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([CH2:13][CH3:14])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc(Br)c2c(c1)CC(CO)O2
Product: CCc1cc(Br)c2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)O2
Yield: 93.7 %

Procedure:
To a solution of 4-ethylphenol (10.0 g, 82.0 mmol) in acetonitrile (250 mL) cooled to 0° C. was slowly added N-bromosuccinimide (16.0 g, 90 mmol) and the reaction mixture was allowed to stir at 0° C. for 1 h. The solvent was removed in vacuo and the reaction mixture was diluted with ice water (500 mL) and diethyl ether (500 mL). A solid precipitate was removed via filtration and the aqueous phase was separated and extracted with ethyl ether (2×200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) gave 8.35 g (51%). Treatment of 2-bromo-4-ethylphenol (8.35 g, 41.0 mmol) with potassium carbonate (14.3 g, 100 mmol) and allyl bromide (6.57 g, 130 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-ethylphenol. Treatment of 2-allyl-6-bromo-4-ethylphenol (5.18, 22.0 mmol) with 3-chloroperoxybenzoic acid (8.60 g, 33.0 mmol, 77%) followed by potassium carbonate (7.4 g, 55.0 mmol) generally according to the procedure described for Intermediate 9 afforded 3.94 g (70%) of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (3.94 g, 15.0 mmol) with p-toluenesulfonyl chloride (3.5 g, 18.0 mol) generally according to the procedure described for Intermediate 10 gave 5.78 g (92%) of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-ethyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.30 g, 2.19 mmol) generally according to the procedure described for Intermediate 35 afforded 0.30 g, (97%) of (±)-(5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.23 g, 3.55 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (77%) of (±)-2-(azidomethyl)-5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.786 g, 0.869 mmol) according to the procedure described in Example 154 afforded 0.009 g (4%) of (±)-[(5-ethyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 198° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14]Br.[H-].[Na+].CC(O)C>CCOCC.CS(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([C:7]#[N:8])[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
A solution of 3.37 g (22.2 mmol) of 4-Chlorobenzyl cyanide and 4.93 g (24.4 mmol) of 1,3-dibromopropane in 15 mL of ether was added dropwise into 1.17 g (48.8 mmol) of NaH in 60 mL of DMSO. The temperature was held between 25° and 35° by water bath cooling. The mixture was stirred at room temperature for 18 hours. The mixture was cooled in ice water and 3 mL of 2-propanol was added dropwise, followed by the addition of 50 mL of water. The mixture was extracted with hexane (3×100 mL), and the combined extracts were washed with water (3×75 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 2.9 g (70%) product as colorless oil. 1H NMR (CDCl3) δ 2.04-2.15 (m, 1H), 2.39-2.52 (m, 1H), 2.55-2.65 (m, 2H), 2.79-2.88 (m, 2H), 7.38 (s, 4H). 13C NMR (CDCl3) 17.3, 34.9, 40.0, 124.2 127.3, 129.4, 134.1, 138.6.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.FC1C(O)=C(F)C(F)=C(F)C=1F.[C:25]([N:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:33][C:34]([OH:36])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH2:56]>C(Cl)Cl>[CH3:52][O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH:56][C:34](=[O:36])[CH2:33][N:32]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a stirring suspension of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol) in reagent grade CH2Cl2 (20 mL) was added a solution of pentafluorophenol (1.5 g, 8.1 mmol) in CH2Cl2 (10 mL) followed by a solution of N-Boc-N-Benzyl glycine 3 [Naylor 1993] (1.32 g, 5.0 mmol) in CH2Cl2 (20 mL). The solution was stirred at ambient temperature for 1 h then triethylamine (2.5 mL, 18 mmol) was added with additional CH2Cl2 (10 mL). The (±)-phenylalanine methyl ester hydrochloride (1.32 g, 5 mmol) was then added in small portions. The final solution was stirred for 20 h at ambient temperature and then was washed with aqueous sodium carbonate (1 M, 100 mL), aqueous citric acid (1 M, 100 mL) and water (50 mL). The organic phase was dried (K2CO3) and concentrated to afford the crude product. Column chromatography of the crude material (silica gel, EtOAc:hexanes, gradient 1:3 3:2) to provided 5 as a clear viscous oil (2.17 g, 102%, solvent heavy). 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 2.99-3.16 (bm, 2H), 3.72 (s, 3H), 3.79 (bd, J=16.1 Hz, overlapped with bm, 2H), 4.30-4.50 (bm, 2H), 4.85 (m, 1H), 6.27 (bs, 0.3H), 6.63 (bs, 0.3H), 7.05-7.11 (bm, 2H), 7.17-7.34 (m, 8H); 13C NMR (100 MHz, CDCl3): δ 28.2, 37.8, 50.2, 51.2 (v. broad), 52.3, 52.8 (broad), 81.1, 127.1, 127.6, 128.1 (broad), 128.6, 129.1, 135.6, 136.9, 155.3 (broad), 168.9 (broad), 171.5.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:9][C@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:3]1[CH2:2][NH:1][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1
Reactant: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CN
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC[C@H](C)[C@@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of rac-cis-Allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (1.36 g, 6.43 mmol), 2-chloro-5-(trifluoromethyl)pyridine (1.75 g, 9.645 mmol), and Cs2CO3 (4.2 g, 12.86 mmol) in DMF (20 mL) was stirred at 80° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound. ESI-MS (m/z): 358, [M+1]+.
Reaction SMILES: [BH4-].[Na+].S(=O)(=O)(O)O.[CH2:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>CCOCC.O1CCCC1.CO>[CH2:8]([C:11]1[CH:19]=[CH:18][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of sodium borohydride (2.9 g, 76 mmol) and concentrated sulfuric acid in ether (prepared by adding 2.0 ml of concentrated sulfuric acid to 4.0 ml of ether) was added dropwise to a solution of p-n-propylbenzoic acid (5.0 g, 32 mmol) in tetrahydrofuran (20 ml) cooled to 0° C. keeping the temperature of the reaction system below 20° C., and then this mixture was stirred at room temperature for 3 hours. After the mixture was cooled on ice, methanol and 1 N sodium hydroxide were added, and this mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give the title compound (4.33 g). This compound was used in the following reaction without purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:39][CH3:40])=[CH:36][N:37]=5)[N:32]=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)=[N:13][N:12]=2)[S:8][CH:7]=1)(=O)C.C1COCC1.CO.[OH-].[Li+]>O>[CH3:40][O:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([O:28][C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:14]4[C:15]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:11]([C:9]5[S:8][CH:7]=[C:6]([CH2:5][OH:4])[CH:10]=5)=[N:12][N:13]=4)=[CH:23][CH:24]=3)=[CH:30][CH:31]=[N:32]2)=[N:37][CH:36]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(COC(C)=O)cs5)c5ccccc45)cc3)ccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(CO)cs5)c5ccccc45)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A scintillation vial was charged with (5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methyl acetate (137 mg, 249 μmol), 1.0 mL 3:1:1 THF:MeOH:water and lithium hydroxide (47.8 mg, 1994 μmol). The homogeneous mixture was stirred at RT for 2 h. Water was added to the mixture, and the precipitated solids were filtered, washed with water, and dried. The crude solids were purified by reverse phase chromatography, Gilson, 10-90% 0.1% TFA/ACN in water to provide (5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methanol. MS: [M+H]=508.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9]=[CH:10][S:11][C:12]=2[C:13]2[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C1(C)C(C)=CC=CC=1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[C:7]([C:8]3[N:9]=[CH:10][S:11][C:12]=3[C:13]3[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1ncccc1-c1ncsc1-c1cccnc1Cl
Solvent: Cc1ccccc1C
Product: COc1ccc(CNc2ncccc2-c2ncsc2-c2cccnc2Cl)cc1
Temperature: 130 °C
Yield: 24.1 %

Procedure:
A mixture of 4,5-di-(2-chloropyridin-3-yl)thiazole (0.047 g), 4-methoxybenzylamine (0.021 g), and diisopropylethylaamine (0.025 g) in xylene was heated in a sealed tube at 130° C. for 4 days. The solvent was evaporated, and the residue was fractionated by chromatography to give 4-[2-(4-methoxybenzylamino)pyridin-3-yl]-5-(2-chloropyridin-3-yl)thiazole (0.015 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](O)=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH2:14]([O:16][C:17](=[O:31])[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[CH2:14]([O:16][C:17](=[O:31])[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:19][NH:20][C:11](=[O:12])[CH2:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:15]
Reactant: CCOC(=O)C(CN)c1ccc(OC)c(OC)c1
Reactant: COc1cc(C)cc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CNC(=O)Cc1cc(C)cc(OC)c1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
A solution of (3-methoxy-5-methyl-phenyl)-acetic acid (512.8 mg, 2.84 mmol), 3-amino-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester (825 mg, 2.84 mmol), and triethylamine (912 uL, 6.54 mmol) in dry methylene chloride (25 mL) was chilled in an ice bath under argon. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 2.98 mmol) was added in one portion and the mixture stirred at room temperature for 72 hrs. The reaction mixture was poured into ethyl acetate (100 mL) and extracted with 2.5% aqueous potassium bisulfate (3×20 mL), 5% aqueous sodium bicarbonate (3×20 mL), and saturated aqueous sodium chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3,4-dimethoxy-phenyl)-3-[2-(3-methoxy-5-methyl-phenyl)-acetylamino]-propionic acid ethyl ester as a light tan foam (0.79 g, 67%). This material was used without further purification: 1H NMR (300 MHz) compatible.
Reaction SMILES: [Br:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[O:6][C:7](C(O)=O)=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1.C(=O)=O>>[Br:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[O:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1
Reactant: COc1cc2oc(C(=O)O)c(C(=O)O)c2cc1Br
Agent: O=C=O
Product: COc1cc2occ(C(=O)O)c2cc1Br
Yield: 88.8 %

Procedure:
5-Bromo-6-methoxybenzo[b]furan-2,3-dicarboxylic acid (D12) (0.85 g, 2.7 mmoles) was heated to its melting point (~270° C.) for 15 mins (CO2 evolution). The mixture was allowed to cool and the resulting black residue extracted with ethyl acetate. The organic solution was then filtered and the filtrate evaporated to dryness to give the title compound (D13) (0.65 g, 89%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C@@H:11](O)[CH2:12][CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C@H:13]([CH2:12][CH:11]=[CH2:10])[CH3:14]
Reactant: Oc1cc(Cl)ccc1Br
Reactant: C=CC[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(Cl)ccc1Br
Reaction time: 20 h
Yield: 92.1 %

Procedure:
To a solution of 2-bromo-5-chlorophenol (0.40 g, 1.93 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.397 mL, 3.86 mmol, 2 equiv), and PPh3 (1.01 g, 3.86 mmol, 2 equiv) in THF (6.4 mL) was added DEAD (0.61 mL, 3.86 mmol, 2 equiv). After stirring 20 h, reaction diluted with ether and washed with 1 N NaOH. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-10% EtOAc in hexane) to provide the product as a colorless oil (0.49 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.3 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 6.83 (dd, J=8.5, 2.3 Hz, 1H), 5.90 (ddt, J=17.1, 10.1, 7.2 Hz, 1H), 5.21-5.11 (m, 2H), 4.49-4.39 (m, 1H), 2.60-2.50 (m, 1H), 2.48-2.38 (m, 1H), 1.37 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[NH2:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15]>>[OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15])=[O:5]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)[C@@](C)(O)c2ccccc2)c2cccc(N)c2-c2ccccc21

Procedure:
Following one or more of the general procedures outlined above, using (S)-(+)-2-hydroxy-2-phenylpropionic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 458 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:24]3[CH2:27][C@H:26]([CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.[NH4+].[Cl-]>[CH3:28][C@@H:26]1[CH2:27][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Temperature: 25 °C

Procedure:
To a solution of cis-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (20.0 mg, 0.0370 mmol) in THF (1 mL) at −78° C. was added 1.0 M of LiAlH4 in THF (0.15 mL), and the mixture was allowed to warm to rt. Once the reaction was complete, a few drops of sat. NH4Cl was added to quench. The material was transferred to a separatory funnel, and extracted using DCM and sat. NaHCO3. The aqueous layer was washed twice with DCM, and the organic fractions were combined and concentrated in vacuo. The material was dissolved in minimal MeOH/DCM, and loaded onto a prep TLC plate, eluting with 2% (7N NH3 in MeOH)/DCM. The band containing the product was collected, and the material was filtered off by washing with 1:1 MeOH I DCM. The filtrate was concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, CDCl3): δ=1.14 (d, J=6.3 Hz, 3H), 2.13-2.23 (m, 2H), 2.46-2.57 (m, 1H), 2.58-2.67 (m, 2H), 3.52-3.62 (m, 1H), 5.07 (br. s., 2H), 7.02-7.10 (m, 3H), 7.10-7.18 (m, 4H), 7.35-7.41 (m, 2H), 7.61-7.66 (m, 2H). MS (ES+): m/z 371.06 (100) [MH+]. HPLC: tR=2.67 min (polar—5 min).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1.[NH2:17][C:18]1[S:19][C:20]([C:30]([NH2:32])=[O:31])=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[Cl:29][C:25]1[CH:24]=[C:23]([C:21]2[N:22]=[C:18]([NH:17][C:7]3[CH:6]=[C:5]([CH2:4][CH:3]([O:15][CH3:16])[O:2][CH3:1])[CH:10]=[CH:9][C:8]=3[N+:11]([O-:13])=[O:12])[S:19][C:20]=2[C:30]([NH2:32])=[O:31])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(Cc1ccc([N+](=O)[O-])c(F)c1)OC
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(Cc1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1)OC
Reaction time: 3 h
Yield: 51.4 %

Procedure:
A mixture of 0.625 g (2.73 mmole) of 4-(2,2-dimethoxy-ethyl)-2-fluoro-1-nitro-benzene (IV.9b), 0.630 g (2.73 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 2.66 g (8.2 mmole) of cesium carbonate and 10 mL of dimethylformamide was stirred at 60 degrees for 3 hours. The mixture was cooled, poured into 50 mL of dilute ammonium chloride solution. The resulting suspension was extracted three times with 20 mL of ethyl acetate. The combined organic layers were washed three times with 20 mL of water, once with 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether to give 0.650 g of 4-(3-chloro-phenyl)-2-[5(2,2-dimethoxy-ethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.9a) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[CH:18][C:17]=2[NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:31])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[CH:18][C:17]=2[NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(OC3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(OC3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-carbamoyl)benzylthio)propanoate (190 mg, 0.20 mmol, 1.00 equiv, 80%) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 82.4 mg (57%) of as a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.94 (d, J=3 Hz, 1H), 8.30 (s, 1H), 8.22 (d, J=9 Hz, 1H), 7.89-7.85 (m, 2H), 7.77 (d, J=9 Hz, 1H), 7.70 (s, 1H), 7.66-7.52 (m, 4H), 7.48-7.43 (m, 2H), 7.19-7.15 (q, J=9 Hz, 1H), 4.69 (s, 3H), 4.01-3.95 (m, 2H), 3.86 (s, 2H), 3.66-3.58 (m, 2H), 2.73-2.68 (m, 2H), 2.59-2.54 (m, 2H), 2.06 (m, 2H), 1.80-1.76 (m, 2H). MS (ES, m/z): 694 [M+H]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:11]1.O>CS(C)=O>[O:9]1[C:10]2([CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:11]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCC2(CO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (3.1 g) in dimethyl sulfoxide (40 mL) was added sodium hydride (570 mg), and the mixture was stirred at room temperature for 1 hr. A solution of benzyl 3-oxopiperidine-1-carboxylate (3.0 g) in dimethyl sulfoxide (10 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 16 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the object product (1.9 g, 60%).