Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C[O:3][CH2:4][C:5]([O:7][CH2:8]C)=O.[CH3:10][C:11]([CH3:13])=[O:12].COC(C)(C)C>C1(C)C=CC=CC=1>[CH3:8][O:7][CH2:5][C:4](=[O:3])[CH2:10][C:11](=[O:12])[CH3:13]
Reactant: CCOC(=O)COC
Reactant: CC(C)=O
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: COCC(=O)CC(C)=O
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of sodium (5.83 g, 243.3 mmol) in dry toluene (62.5 mL) was added ethyl (methyloxy)acetate (24 g, 203.4 mmol) at −5° C. After stirring for 3 h, acetone (14 g, 231.4 mmol) was slowly added, upon which the mixture became brown and viscous. Next added 72 mL of tert-butyl methyl ether, and the reaction mixture was stirred at room temperature for 12 h, after which time the sodium salt precipitated. After collection and washing with additional tert-butyl methyl ether, the sodium salt was dissolved in 46 mL of 20% H2SO4. The contents were extracted with tert-butyl methyl ether and the organic layers concentrated to afford 1-(methyloxy)-2,4-pentanedione (9.76 g, 36.9%). 1H NMR (400 MHz, CDCl3-d3) δ 5.76 (s, 1H), 3.96 (s, 2H), 3.38 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)NC(=O)c3cccnc3)cc1)n2C)c1ccccn1
Yield: 56 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and nicotinic acid chloride. Yield: 56% of theory, C34H33N7O4 (603.7) Rf value: 0.52 (silica gel; dichloromethane/methanol=9:1) ##EQU97##
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[N:14]1C=CC=C[CH:15]=1.N>CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][O:12][C:5]1([C:15]#[N:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:2]=[CH:3][CH2:4]1
Reactant: c1ccncc1
Reactant: COc1ccc(Br)c2c1CCCC2
Agent: N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1(C#N)CC=CC2=C1CCCC2

Procedure:
4-Bromo-1-methoxy-5,6,7,8-tetrahydronaphthalene (1) (2.5 g, 10.4 mM) cuprous cyanide (1.07 g, 5.4 mM), pyridine (1.5 ml) and hexamethylphosphoramide (0.3 ml) were stirred at 192° C. for 16 hours. The mixture was poured into aqueous ammonia and extracted with ether. The ether was washed with ammonia, water, dilute hydrochloric acid and then saturated brine. The ether solution was then dried and evaporated to give the nitrile (2) (1.90 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Br:9])=[CH:7][CH:8]=1.[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:4]=1[F:20])=[O:28]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: Cc1nc(Br)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)c(C(=O)NCc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A mixture of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.141 mmol), 4-bromo-2-methyl-1H-imidazole-5-carboxylic acid (0.029 g, 0.141 mmol), HATU (0.064 g, 0.169 mmol) and DIPEA (0.029 mL, 0.169 mmol) in DMF (1 mL) was stirred at RT overnight. The reaction mixture was extracted with EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by preparative LCMS (acetonitrile:water with 0.1% formic acid) to give the title compound (15 mg, 19.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 (br. s., 1H), 7.77 (s, 1H), 7.57 (d, 1H), 7.45 (s, 1H), 7.40 (d, 1H), 7.25 (t, 1H), 4.18-4.59 (m, 2H), 2.21 (s, 3H). ES MS: m/z 541, 543.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.[CH3:18][S:19]SC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([S:19][CH3:18])[C:3]=1[F:9]
Reactant: Fc1cc(Cl)ccc1Br
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 94 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in THF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50° C. After addition, the solution was warmed to −20° C. and then cooled to −50° C. and a solution of dimethyldisulfide (18.8 g, 0.20 mol) in THF (50 mL) was slowly added and the mixture was warmed to ambient temperature. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (2×150 mL) and the combined organic phases dried (sodium sulfate) and concentrated. The residual red oil was purified by chromatography (5% ethyl acetate in hexanes) to give 1-bromo-4-chloro-2-fluoro-3-(methylthio)benzene (23.9 g, 0.094 mol): 1H NMR (CDCl3): δ 7.40 (m, 1H), 7.15 (dd, 1H), 2.50 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:13]([C:14]([C:25](=[O:38])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3C3C=CC=CC=3)=[C:15]([CH2:23][CH3:24])[C:16]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CCCCCC>[C:25]([C:14]1[N:13]2[C:17]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=[CH:12]2)=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15]=1[CH2:23][CH3:24])(=[O:38])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1c(CC)c(C(=O)c2ccccc2-c2ccccc2)n2cccc(OCc3ccccc3)c12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CC)c(C(=O)c2ccccc2)n2cccc(OCc3ccccc3)c12
Yield: 79 %

Procedure:
Mp, 124-125° C. (AcOEt-hexane). 79% Yield. Ethyl (8-benzyloxy-2-ethyl-3-(o-phenylbenzoyl)indolizin-1-yl)carboxylate 26b. Mp, 110-112° C. (ether-hexane). 46.0% Yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=[O:30].[K+].[K+].OO>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]([NH2:25])=[O:30])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)CC1=O
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C(N)=O)(c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenylpiperidin-4-yl)-2,2-dimethylpropanenitrile (11 mg, 0.025 mmol) in DMSO (3 mL) were added K2CO3 (6.9 mg 0.05 mmol) and 30% H2O2 (5.7 mg 0.05 mmol). The mixture was stirred at rt overnight. After being diluted with water (2 mL), the mixture was washed with EtOAc (3×2 mL). The aqueous layer was acidified to pH=3-4, and extracted with EtOAc (3×2 mL). The combined organic layers were washed with brine (3×2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was dried under vacuum and purified by TLC and preparative HPLC to give 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-2-oxo-4-phenylpiperidin-4-yl)-2,2-dimethylpropanamide (8 mg, 70%). LC-MS Method 2 tR=1.36 min, m/z=481, 479, 459, 457; 1H NMR (CDCl3): δ 0.78 (s, 3H), 1.08 (s, 3H), 1.40 (d, 3H), 2.0 (m, 4H), 2.18 (m, 1H), 2.66 (m, 1H), 2.81 (m, 1H), 3.32 (m, 1H), 5.58 (m, 1H), 5.84 (m, 1H), 6.18 (m, 1H), 6.68 (m, 2H), 7.16 (m, 2H), 7.20 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]([CH2:35][CH2:36][OH:37])[C:28](=O)[O:29]C(C)(C)C)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[N:27]3[CH2:35][CH2:36][O:37][C:28]3=[O:29])[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N(CCO)C(=O)OC(C)(C)C)no2)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N3CCOC3=O)no2)cc1C#N
Reaction time: 20 h
Yield: 29 %

Procedure:
To a stirred solution of (R)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate INT-22 in DMF (1 mL) was added NaH (6 mg, 0.15 mmol, of a 60% solution in mineral oil). After stirring for 20 h, the reaction mixture was diluted with EA and washed with NaHCO3. The combined aqueous extracts were back-extracted with EA. The combined organic extracts were dried over Na2SO4, concentrated, and purified by column chromatography (EA/hexanes) to provide 11.9 mg (29%) of (R)-2-isopropoxy-5-(3-(1-(2-oxooxazolidin-3-yl)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 154. LCMS-ESI (m/z) calculated for C22H22N4O4: 430.5; found 431.1 [M+H]+, tR=3.72 min. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.2 Hz, 1H), 8.34 (dd, J=8.9, 2.2 Hz, 1H), 8.14 (t, J=4.4 Hz, 1H), 7.42 (m, 2H), 7.13 (d, J=9.0 Hz, 1H), 5.72-5.57 (m, 1H), 4.80 (dt, J=12.2, 6.1 Hz, 1H), 4.35 (qt, J=15.7, 7.8 Hz, 2H), 3.56-3.39 (m, 2H), 3.25 (dtd, J=24.4, 8.6, 7.1 Hz, 2H), 2.65-2.48 (m, 1H), 2.10 (ddt, J=13.7, 9.0, 7.1 Hz, 1H), 1.48 (d, J=6.1 Hz, 6H). Compound 155 was made in an analogous fashion.
Reaction SMILES: [CH3:1][Li].[CH2:3]([O:5][C:6]1[O:11][C:10](=[O:12])[C:9]2[C:13]([CH2:17]Br)=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:4]>CCOCC.O1CCCC1>[CH2:3]([O:5][C:6]1[O:11][C:10](=[O:12])[C:9]2[C:13]([CH2:17][CH3:1])=[CH:14][CH:15]=[CH:16][C:8]=2[N:7]=1)[CH3:4]
Reactant: [Li]C
Reactant: CCOc1nc2cccc(CBr)c2c(=O)o1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1nc2cccc(CC)c2c(=O)o1
Temperature: -25 °C
Reaction time: 0.42 h

Procedure:
Methyl lithium (4.69 ml, 1.4M, Aldrich) was added to a suspension of cuprous iodide (0.62 gm) in anhydrous ether under argon at -78° C. The solution was stirred at -25° C. for 25 min. This solution was added to a solution of 2-ethoxy-5-bromomethyl-4H-3,1-benzoxazin-4-one (200 mg) in 15 ml anhydrous ether and 3 ml dry tetrahydrofuran at -60° C. Reaction was monitored by TLC until reaction completion. The reaction was quenched with saturated ammonium chloride solution and filtered. The filtrate was extracted in the usual manner. The ethereal layer was washed with water, dried over magnesium sulphate and evaporated to give an oil. The material was purified by thick layer chromatography (Rf =0.75, 3-% ethyl acetate: petroleum ether), to give 2-ethoxy-5-ethyl-4H-3,1-benzoxazin-4-one, m.p. 89°-91° C., H NMR: 1.3, 1.5 (2t, 6H, 2CH3), 3.2 (q, 2H, CH2), 4.5 (q, 2H, OCH2CH3), 7.2 (m, 2H, ArH), 7.6 (t, 1H, ArH).
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[CH3:39][O:38][C:36](=[O:37])[C@@H:20]([NH:19][C:18]([C@@H:17]1[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:40])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]-isoquinoline-7-carboxylic acid tert-butyl ester (300 mg) was dissolved in 15 mL DCM and 7.5 mL 4N HCl (in dioxane) added. The reaction was stirred at room temperature for 2.5 hours, DCM was added and mixture was concentrated. The solid was suspended in EtOAc-THF (9:1) and washed with a 10% sodium carbonate solution. The organic layer was washed with brine, and dried over sodium sulfate and concentrated. DCM added and the mixture concentrated to provide 0.2 g of the product. LCMS: m/z 753.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][NH:15][CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(O[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=O)(=O)C.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)=O)C>[C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH3:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CNCC1CCc2ccc(NC(C)=O)cc21
Reactant: CS(=O)(=O)OCCCCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CC(=O)Nc1ccc2c(c1)C(CN(C)CCCCC1CCCCC1)CC2

Procedure:
A mixture of 6-Acetylamino-1-(N-methylaminomethyl)indan (1.5 g), 4-cyclohexylbutan-1-ol mesylate (2.5 g), potassium carbonate (1.4 g), and a crystal of potassium iodide in MIBK (80 ml) were refluxed for 5 h. After cooling inorganic salts were filtered off and the solvent evaporated in vacuo. The remaining oil was subjected to column chromatography on SiO2 (eluted with ethyl acetate:heptane:triethylamine 80:20:4). The free base of the title compound was isolated as an oil. The sesquioxalate of 13a crystallized from acetone. Yield 1.6 g Mp: 145°-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:27]Br>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[N:10][S:11][C:12]=2[C:13]2[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[C:17]([Br:27])[CH:18]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCNc1ncccc1-c1snnc1-c1cccnc1Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCNc1ncc(Br)cc1-c1snnc1-c1cccnc1Cl
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
To a solution of 4-(2-chloropyridin-3-yl)-5-(2-ethylaminopyridin-3-yl)-1, 2, 3-thiadiazole (0.324 g) in acetic acid (4 mL) containing sodium acetate (0.098 g) was added dropwise a solution of bromine (0.185 g) in acetic acid (1 mL). After 5 minutes, the mixture was diluted with ethyl acetate, washed with aqueous potassium carbonate, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane/chloroform 1/3/0.5) gave 4-(2-chloropyridin-3-yl)-5-(2-ethylamino-5-bromo-pyridin-3-yl)-1, 2, 3-thiadiazole (0.329 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH:14]C(OCC2C=CC=CC=2)=O)[CH:11]=[CH:10][C:9]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1)(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2ccc(NC(=O)OCc3ccccc3)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(N)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 5-benzyloxycarbonylamino-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.35 g) in tetrahydrofuran (4 mL) was added 10% palladium-carbon powder (0.07 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. An insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/3-dichloromethane/ethyl acetate=1/1) to give 5-amino-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.19 g).
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.[N+:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](C(O)=O)=[CH:32]2)([O-:28])=[O:27].CCN=C=NCCCN(C)C.Cl.CC(N(C)C)=O>Cl>[Cl:25][CH2:24][CH:10]1[C:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:16]=2[N:8]([C:6]([C:33]2[NH:34][C:35]3[C:31]([CH:32]=2)=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:37][CH:36]=3)=[O:7])[CH2:9]1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C(c1cc2cc([N+](=O)[O-])ccc2[nH]1)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of 13 (280 mg, 0.77 mmol) in HCl-saturated dioxane (10 mL) was stirred at 10° C. for 2 h, then evaporated to dryness under reduced pressure below 30° C. 5-Nitroindole-2-carboxylic acid [S. M. Parmerter, J. Amer. Chem. Soc. 80, 1958, 4621-4625] (167 mg, 0.81 mmol) EDCI.HCl (370 mg, 1.93 mmol) and DMA (3 mL) were then added and the mixture was stirred at 20° C. for 2 h. Addition of dilute KHCO3 precipitated a yellow solid which was collected, washed well with water and recrystallised from THF to give 14b (282 mg, 81%), mp >300° C. 1H NMR [(CD3)2SO] δ 12.56 (s, 1 H, NH), 9.14 (s, 1 H, H-4), 8.74 (d, J=2.2 Hz, 1 H, H-4'), 8.35 (dd, J=7.0, 2.7 Hz, 1 H, H-6), 8.24 (dd, J=6.8, 2.7 Hz, 1 H, H-9), 8.12 (dd, J=9.1, 2.3 Hz, 1 H, H-6'), 7.80-7.72 (m, 2 H, H-7,8), 7.64 (d, J=9.1 Hz, 1 H, H-7'), 758 (s, 1 H, H-3'), 4.96 (t, J=10.1 Hz, 1 H, H-2), 4.71 (dd, J=10.8, 2.3 Hz, 1 H, H-2), 4.68-4.61 (m, 1 H, H-1), 4.18-4.09 (m, 2 H, CH2Cl).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])#[N:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CCOCC>[CH2:25]([C:4]1[C:3]([C:1]#[N:2])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:5]=1[CH3:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)Nc2c(C)cc(C#N)cc2C(=O)O)cc1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)Nc2c(C(=O)O)cc(C#N)c(Cc3ccccc3)c2C)cc1
Yield: 51 %

Procedure:
In the same manner as described in Example 177, 4.5 g (13 mmol) of the product of Example 180 and 5 mL of benzylbromide provided 3.5 g (51%) of the desired product as brown solid after trituration with ether. m.p. 123° C.; Electrospray Mass Spec 527 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.[NH2:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][N:23]=1>>[OH:28][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([NH:21][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])[CH:27]=1
Reactant: O=C(O)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: Nc1cc(O)ccn1
Product: O=C(Nc1cc(O)ccn1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21

Procedure:
A solution of 4-methoxypyridin-2-amine (100 mg, 0.806 mmol) in DCM (1.6 mL) under N2 atmosphere was cooled in an dry ice/IPA bath, and tribromoborane (0.305 mL, 3.23 mmol) was added with a syringe. After removing the cold bath, the reaction was stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL) and stirred for an additional 30 min. It was then washed with saturated NaHCO3 (20 mL) to pH=7 and extracted with DCM (3×20 mL). The combined organic layer was dried over MgSO4 and concentrated to provide 2-aminopyridin-4-ol. The title compound was prepared in a manner similar to that described in Method EE using Intermediate 1 (see Example 1.1) and 2-aminopyridin-4-ol. LCMS m/z=369.3 [M+H]+; 1H NMR: (400 MHz, CD3CN) δ ppm 0.50 (td, J=4.7 and 3.5 Hz, 1H), 1.22 (td, J=7.8 and 4.9 Hz, 1H), 2.21-2.26 (m, 1H), 2.31-2.38 (m, 1H), 2.93 (d, J=16.7 Hz, 1H), 3.05 (dd, J=16.6 and 6.3 Hz, 1H), 6.80 (dd, J=7.1 and 2.2 Hz, 1H), 6.95 (d, J=2.2 Hz, 1H), 7.15-7.21 (m, 1H), 7.22-7.29 (m, 1H), 7.52 (s, 1H), 7.70 (td, J=8.8 and 5.9 Hz, 1H), 7.82 (d, J=7.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([CH:7]=[O:8])[CH2:5][CH3:6].[Cl:10][CH2:11][CH2:12]O>C1C=CC=CC=1.S(=O)(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH2:5][CH3:6])=[CH:7][O:8][CH2:12][CH2:11][Cl:10]
Reactant: CCC(C=O)C(=O)OC
Reactant: OCCCl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(=COCCCl)C(=O)OC
Yield: 82.3 %

Procedure:
35 g 2-Formyl-butyric acid methyl ester (0.27 mole) was dissolved in 250 ml benzene, and the solution was mixed with 26 g 2-chloroethanol (0.324 mole) and 700 mg sodium bisulfate. The mixture was refluxed for 18 hours, and the water formed during the reaction was withdrawn continuously. After removal of the solvent by distillation, the residue was fractionated in a vacuum and 42.8 g (44.2 g) 3-(2-chloroethoxy)-2-ethylacrylic acid methyl ester boiling at 99°-101° C./3 torr was obtained (82.4%-85% yield). nD23 =1.4770.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.CO.[ClH:31].C[CH2:33][O:34]CC>C(Cl)(Cl)Cl>[ClH:31].[C:4]1(=[O:23])[N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[CH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:34][CH3:33])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: N#Cc1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=N)c1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.7 g of 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzonitrile in 100 ml of chloroform was added at room temperature slowly dropwise 30 ml of anhydrous methanol saturated with anhydrous hydrogen chloride. The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of methyl 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzimidate hydrochloride; m.p. 230°-234° C. (decomp.).