Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10]Br.[C:12]1([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH:13]=1.CCN(C(C)C)C(C)C>CC#N>[Br-:1].[F:9][C:5]1[C:4]2[CH2:10][CH:13]3[C:12](=[N+:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH:16]([CH2:2][C:3]=2[CH:8]=[CH:7][CH:6]=1)[CH2:15][CH2:14]3
Reactant: C1=C(N2CCCC2)CCC1
Reactant: Fc1cccc(CBr)c1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1cccc2c1CC1CCC(C2)C1=[N+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.3 %

Procedure:
A solution of 1,2-bis-bromomethyl-3-fluoro-benzene (4.4 g, 15.6 mmol) in MeCN (10 ml) was added to stirred solution of 1-cyclopent-1-enyl-pyrrolidine (2.3 ml, 15.6 mmol) and DIPEA (5.4 ml, 31.2 mmol) in MeCN (20 ml). The mixture was stirred at room temperature for 18 hours and then filtered. Washing with cold MeCN afforded an off-white solid 1.02 g (19%). m/z 258 (M+).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:24]=1
Reactant: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 22 (3.23 g, 8.33 mmol) and NiCl2.6H2O (3.96 g, 16.66 mmol) in MeOH/THF (100/100 mL) was added NaBH4 (1.24 g, 33.32 mmol). The reaction mixture was stirred for 1 hr, concentrated to dryness and the resultant solid was dissolved in 10% HCl. The aqueous solution was then made basic with concentrated NH4OH solution and extracted with EtOAc. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 23 as a black solid (2.72 g, 91% yield). MS (m/z): 358.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14]([OH:16])=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH2:46][CH2:47][NH2:48]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:48][CH2:47][CH2:46][C:45]1[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:43]([O:42][CH3:41])[CH:44]=1)=[O:16])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: COc1ccc(CCNC(=O)[C@H](Cc2ccc(OCC(=O)O)c(C(=O)O)c2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1OC
Yield: 9.6 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and 3,4-dimethoxyphenethylamine (52 mg, 0.29 mmol) according to Method C with HPLC purification to give the title compound (12 mg). 1H-NMR (400 MHz, CD3OD) δ 1.38 (s, 9H) 2.68 (t, 2H) 2.72-3.09 (m, 4H) 3.29-3.44 (m, 2H) 3.80 (s, 3H) 3.85 (s, 3H) 4.25 (m, 1H) 4.52 (m, 1H) 4.79 (s, 2H) 6.74 (d, 1H) 6.84 (s, 1H) 6.87 (d, 1H) 7.06 (d, 1H) 7.17-7.38 (m, 6H) 7.73 (s, 1H); HRMS m/z 693.2904 (calc of monoisotopic mass for C36H43N3O11 gives 693.2898).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1.[F:34][C:35]([F:50])([F:49])[C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39](O)=[O:40]>>[F:34][C:35]([F:49])([F:50])[C:36]1[CH:37]=[C:38]([C:39]([NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=2)=[O:40])[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](c2ccc(F)c(F)c2)C1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccc(F)c(F)c2)C1

Procedure:
sing the compound obtained in step 1 and 3,5-bis(trifluoromethyl)benzoic acid, and by the reaction and purification in the same manner as in Reference Example 1, step 5, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([OH:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(O)c1ccc(C)nc1
Reaction time: 6 h

Procedure:
10.0 g (0.048 mol) of 6-methyl nicotinoyl acetic acid ethyl ester (distilled) was dissolved in 200 ml of 95 percent ethanol, mixed with 1 g of 5 percent palladium on activated carbon and poured into a 1-liter autoclave. The autoclave was put under 10 bars of hydrogen and stirred at 20°. The hydrogenation ended after 6 hours. The autoclave was opened, and the reaction solution filtered and evaporated. 10.0 g of 3-hydroxy-3-(2-methyl-5-pyridyl)-propionic acid ethyl ester remained, which according to NMR and DC was pure. The yield, in relation to the 6-methyl nicotinoyl acetic acid ethyl ester, was 100 percent.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[C:8]#[N:9].C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17]>CCO.C1COCC1>[CH2:16]([O:18][C:19]([C:20]1[S:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]=1[NH2:9])=[O:22])[CH3:17]
Reactant: N#CC1=C(Cl)CCCC1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1sc2c(c1N)CCCC2
Temperature: 90 °C
Yield: 101.4 %

Procedure:
A 250 mL flask was charged with 2-chloro-cyclohex-1-enecarbonitrile (3.0 g, 21 mmol) in a 6:1 mixture of EtOH/THF (42 mL), K2CO3 (2.9 g, 21 mmol), and mercapto-acetic acid ethyl ester (3.5 mL, 32 mmol), after which it was fitted with a reflux condenser under N2 atmosphere and heated to 90° C. for 24 h. The mixture was filtered through a pad of diatomaceous earth, such as Celite®, rinsing thoroughly with MeOH (400 mL). After concentration, the title compound was purified by FCC (60% ethyl acetate (EtOAc)/hexanes) to give an amber-colored oil (4.8 g). MS: 226.1. 1H NMR (400 MHz, CDCl3) δ ppm 5.35 (s, 2H), 2.71-2.64 (m, 2H), 2.36-2.26 (m, 2H), 1.87-1.77 (m, 4H), 1.33 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([S:25][CH3:26])=[C:12]2[CH2:27][C:28]([NH2:30])=[O:29])C.[OH-].[Na+]>C1COCC1.CCO>[NH2:30][C:28](=[O:29])[CH2:27][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:31])=[O:3])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[S:25][CH3:26]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1c(CC(N)=O)c2cc(OCCCC(=O)O)ccc2n1Cc1ccccc1
Yield: 85 %

Procedure:
As described in Example 45, 245 mg (0.56 mmol) of 4-[[3-(2-amino-2-oxoethyl)-2-(methylthio)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid ethyl ester (Example 47) was hydrolyzed with 1 mL of 5N NaOH in 5 mL of THF and 15 mL of EtOH. The crude product was washed with EtOH/ether to give 195 mg (85% yield of 4-[[3-(2-amino-2-oxoethyl)-2-(methylthio)-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoic acid, mp, 187°-188° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(#N)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(NCc3cccnc3)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2.8 g. portion of 3-(4-phenoxyphenylaminomethyl)pyridine was dissolved in 100 ml. of acetonitrile, and to it were added 2 g. of potassium carbonate and 1.3 g. of ethanesulfonyl chloride. The mixture was stirred at ambient temperature for 2 days, and it was then filtered and concentrated under vacuum. The oily residue was chromatographed on silica gel, eluting with 4.1 toluene:acetone. The product-containing fractions were evaporated under vacuum, and the residue was taken up in diethyl ether. Upon standing, a precipitate formed, which was shown to be 2.0 g. of the desired product, m.p. 79°-80°.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:24]=[CH:23][C:11]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)=[CH:10][CH:9]=2)[N:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[C:36]([F:39])([F:38])[F:37]>N1C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=4)=[CH:23][CH:24]=3)[N:7]=2)(=[O:33])=[O:34])=[CH:28][C:27]=1[C:36]([F:39])([F:37])[F:38]
Reactant: CNC(=O)c1cc(Oc2ccc(-c3cnnc(N)n3)cc2)ccn1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: CNC(=O)c1cc(Oc2ccc(-c3cnnc(NS(=O)(=O)c4ccc(Cl)c(C(F)(F)F)c4)n3)cc2)ccn1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
108.6 mg (0.337 mmol, 1.0 equivalent) of 4-[4-(3-amino-[1,2,4]triazin-5-yl)-phenoxy]-N-methylpyridine-2-carboxamide can be dissolved in 2 mL of anhydrous pyridine with heating to about 100° C. 0.405 mmol (1.2 equivalent) of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride can be added. The reaction mixture can be allowed to stir at ambient temperature for 1-2 hours. The product can be isolated by a number of methods known to one skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography, or by reverse-phase preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CNCc1ncccc1Br
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1cccn2cncc12
Temperature: 0 °C
Yield: 63.1 %

Procedure:
A suspension of N-[(3-bromopyridin-2-yl)methyl]formamide (312.0 mg, 1.451 mmol) in toluene (7.0 mL) was charged with phosphorus oxychloride (0.50 mL, 5.4 mmol) and then refluxed for 1 h. The mixture was concentrated. The residue was cooled to 0° C. and water was added slowly. To the cooled aqueous suspension, aqueous ammonium hydroxide was added until the pH was basic, and the mixture was then extracted with ethyl acetate. The organic fraction was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue by ISCO chromatography (100% ethyl acetate) afforded 180.5 mg (63%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=0.51 Hz, 1H), 8.39 (td, J=0.88, 7.07 Hz, 1H), 7.38 (t, J=0.88 Hz, 1H), 7.12 (d, J=7.07 Hz, 1H), 6.60 (dd, J=6.90, 6.90 Hz, 1H); MS (ESI): 197.05, 198.99 [M+H]+; HPLC tR=2.86 min (ZQ3: polar—5 min).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]([CH:11]1[CH:24](O)[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=3)[N:16]=[CH:15][C:14]=2[S:13][CH2:12]1)=[O:10])[CH3:7].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:6]([O:8][C:9]([C:11]1[CH2:12][S:13][C:14]2[CH:15]=[N:16][C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][C:20]([O:26][CH3:27])=[CH:19][CH:18]=3)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1CSc2cnc3ccc(OC)cc3c2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2c(cnc3ccc(OC)cc23)SC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.1 %

Procedure:
Methanesulfonyl chloride (745 μL, 9.63 mmol, 3.0 eq) is added at room temperature to a stirred solution of 4-hydroxy-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester (1.02 g, 3.21 mmol, 1.0 eq) in dichloromethane (10 mL), followed by triethylamine (2.23 mL, 16.05 mmol, 5.0 eq) and 4-(dimethylamino)pyridine (392 mg, 3.21 mmol, 1.0 eq). After 20 minutes stirring at room temperature, solvent is removed and the crude product is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1, v/v) to afford 6-methoxy-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester as a yellow solid (330 mg, 34% yield).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([O:22]C)=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:15]=2)=[CH:7][CH:6]=1>>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([OH:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:15]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(OC)cc3)nc12
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Yield: 92 %

Procedure:
2-(4-Methoxyphenyl)benzoxazole-4-carboxylic acid was prepared via the lithium hydroxide mediated hydrolysis of methyl 2-(4-methoxyphenyl)benzoxazole-4-carboxylate as described in Step B of Example 14. This material was obtained in 92% yield as a white solid: δ 11.90 (br s, 1H), 8.25 (m, 2H), 8.13 (dd, J=7.8, 0.9 Hz, 1H), 7.79 (dd, J=7.8, 0.9 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.08 (m, 2H), 3.93 (s, 3H); MS (ESI) m/z 270 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@@H:16](OS(C(F)(F)F)(=O)=O)[C@@H:15]2[C@H:12]1[C:13](=[O:37])[N:14]2[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C@H:16]([F:41])[C@@H:15]2[C@H:12]1[C:13](=[O:37])[N:14]2[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [F-]
Reactant: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@H](OS(=O)(=O)C(F)(F)F)CN3C(=O)OCc2ccccc2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H]3[C@H]2[C@@H](F)CN3C(=O)OCc2ccccc2)cc1OC

Procedure:
(1S,4R,5S)-6-(3,4-Dimethoxy-benzyl)-7-oxo-4-trifluoromethanesulphonyloxy-2,6-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester (1.1 g, 2.02 mmol) and tetrabutylammonium fluoride trihydrate (704 mg, 2.23 mmol) were stirred together in 10 ml of tetrahydrofuran at room temperature for 10 min. Thereafter, the solvent was removed in a vacuum, the oily residue was taken up in ethyl acetate and extracted three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated. The residual brown oil was chromatographed over silica gel with ethyl acetate and a pale yellow oil was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:15])[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([CH3:14])=[CH:10]2)=[O:4].[OH-].[Na+]>CO>[Cl:15][C:7]1[CH:8]=[C:9]2[C:13](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:12][C:11]([CH3:14])=[CH:10]2
Reactant: COC(=O)c1cc(Cl)cc2cc(C)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2cc(Cl)cc(C(=O)O)c2[nH]1
Yield: 73.4 %

Procedure:
To a solution of 5-chloro-2-methyl-1H-indole-7-carboxylic acid methyl ester (30 mg, 0.13 mmol) in MeOH (5 ml) was added 1N NaOH(aq) (268 μl, 0.27 mmol) and the reaction mixture was refluxed for 2 h. The reaction mixture was concentrated in vacuo and water was added. The aqueous layer was acidified to pH3 using 1N HCl and the aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the desired product (20 mg, 71%) which did not require further purification. MS (ISP) 208.1 (M−H)−.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH2:18][N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1.IC.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[C:15]2[CH:34]=[CH:33][CH:32]=[CH:31][C:16]=2[C:17]2[CH:18]([CH3:1])[N:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:20](=[O:23])[C:21]=2[CH:22]=1
Reactant: O=C1c2cc(Br)c3ccccc3c2CN1c1ccccc1F
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1c2c(cc(Br)c3ccccc23)C(=O)N1c1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (0.30 mL, 2.1 mmol) in 1 mL of tetrahydrofuran cooled to 0° C. was added n-butyllithium (2.5 M tetrahydrofuran solution, 0.93 mL, 2.3 mmol) dropwise. After 30 min, the mixture was added to a −78° C. solution of 5-bromo-2-(2-fluorophenyl)-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.150 g, 0.421 mmol) in 2 mL of tetrahydrofuran. After stirring for 30 min at −78° C., iodomethane (0.026 mL, 0.42 mmol) was added dropwise and after an additional 1 hr, the mixture was warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 2× with ethyl acetate. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the 5-bromo-2-(2-fluorophenyl)-1-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([OH:30])=O)=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:40])=O>C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([Cl:40])=[O:30])=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Solvent: ClCCCl
Product: O=C(Cl)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinic acid (71 mg, 0.133 mmol) in anhydrous ClCH2CH2Cl (1 mL) at room temperature was added dropwise thionyl chloride (2 mL). The mixture was then stirred at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was evaporated with toluene (5 mL×2), and dried in high vacuum to afford the title compound (72 mg) as a yellow foam, which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]2[C:10](B(O)O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[N:7]=1.Br[C:29]1[CH:38]=[C:37]([F:39])[C:32]2[N:33]=[C:34]([CH3:36])[O:35][C:31]=2[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O.Cl[Pd]Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]2[C:10]([C:29]3[CH:38]=[C:37]([F:39])[C:32]4[N:33]=[C:34]([CH3:36])[O:35][C:31]=4[CH:30]=3)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[N:7]=1
Reactant: Cc1nc2c(F)cc(Br)cc2o1
Reactant: C[Si](C)(C)CCOCn1cc(B(O)O)c2c(OC3CCCC3)nc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1nc2c(F)cc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
(2-Chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)boronic acid (1 equiv), 6-bromo-4-fluoro-2-methylbenzo[d]oxazole (1.1 equiv), sodium carbonate (3 equiv) and [1,1′-Bisdiphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (0.1 equiv) were suspended in 1,4-dioxane/water, flushed with nitrogen, and stirred at 90° C. for 2 h. The reaction mixture was purified by silica gel chromatography (0 to 60% ethyl acetate in hexane) to give the title compound (72% yield). MS (ESI) m/z 517.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][CH:7]=[CH:6][CH2:5][CH2:4][C:3]1=[O:10].[CH2:11](O)[CH3:12].C1C=CC=CC=1.C([O-])(=[O:22])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].O>CCOCC>[O:10]=[CH:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][C:2]([O:1][CH2:11][CH3:12])=[O:22]
Reactant: CC(=O)[O-]
Reactant: CCO
Reactant: O=C1CCC=CCCC1O
Agent: [Pb+4]
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC/C=C\CCC=O
Reaction time: 3 h

Procedure:
To 220 mg. of 2-hydroxy-5-cycloocten-1-one in 5 ml. of 30% ethanol/benzene is added 860 mg. of 85% lead tetraacetate in portions. After about 3 hours at room temperature, water and ether are added to the reaction mixture. The aqueous phase is extracted several times with ether. The combined ether extracts are washed with 2M sodium carbonate and saturated sodium chloride solution, dried over calcium sulfate and evaporated to give ethyl (4Z)-8-oxo-4-octenoate in high purity.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[CH2:29][NH:28][CH2:27][CH2:26]2.C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH:7]=[N:8]2)=[C:4]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:29]2)[N:3]=1
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: CC(c1ccccc1)n1cnc2nc(Cl)nc(Cl)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3ncn(C(C)c4ccccc4)c13)CC2
Yield: 38.4 %

Procedure:
Employing the procedure of Preparation B, 730 mg of 2,6-dichloro-7-(1-phenylethyl)purine, 573 mg of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride and 505 mg of triethylamine in 25 ml of dimethylacetamide gave 430 mg of the desired intermediate.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]=[S:18].[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]1[N:5]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:3][S:18]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)CBr
Reactant: [NH3+]CCCl
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC(C)C

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate, which was reacted with isobutyl bromide according to Method D2a to give 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidine.