Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH2:13][C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:17][CH2:18][O:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:7]1([CH:13]([CH2:17][CH2:18][O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]#[N:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)OCCBr
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)OCCC(C#N)c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of potassium tert-butoxide (12.3 g) in toluene (200 mL) was treated dropwise with a mixture of phenylacetonitrile (12.9 g) and (2-bromoethoxy)trimethyl-silane (23.8 g) at room temperature. Upon completion of the addition, the reaction mixture was refluxed for 5 h, then cooled to room temperature and quenched by pouring onto a mixture of ice and water. The formed organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give 2-phenyl-4-trimethylsilanyloxy-butyronitrile. The obtained butyronitrile derivative was redissolved in a mixture of ethanol (40 mL) and 70% aqueous sulfuric acid (40 mL), stirred at 50° C. for 3 h and, after cooling to room temperature, diluted with water (150 mL). The resulted organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, then with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.0 g (62%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:7]([O:19][CH3:20])[CH:6]=1)[OH:4].[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=3)=[C:7]([O:19][CH3:20])[CH:6]=2)[C:2]([F:1])([F:21])[F:22])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C(O)C(F)(F)F)ccc1Oc1cccc(F)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(OS(=O)(=O)c2ccc(C)cc2)C(F)(F)F)ccc1Oc1cccc(F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
To a solution of 2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol (0.52 mmol; 165 mg), tosyl chloride (0.57 mmol; 109 mg) and DMAP (0.01 mmol; 1.5 mg) under argon in dichloromethane (4 mL) at 0° C. was added TEA (1.04 mmol; 145 μl). The reaction mixture was stirred at rt for 3 h, then washed with brine (2×), dried over MgSO4, concentrated and purified by preparative TLC on silica gel (ethyl acetate/cyclohexane—30/70) to yield the title compound (101 mg; 0.21 mmol; 41%).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:18][N:17]=2)=[CH:12][CH:11]=1>>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:18][N:17]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2nsc(S(N)(=O)=O)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1nc(-c2ccc(O)cc2)ns1
Temperature: 0 °C
Yield: 7.5 %

Procedure:
To 35 g of pyridine hydrochloride at 200° was added 28 g of 3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-sulfonamide with stirring. The resulting mixture was maintained at 200°-4° for 10 minutes, cooled slightly, poured into excess ice water and extracted with ethyl acetate (3×). The organics were dried over anhydrous magnesium sulfate and concentrated to give 2.0 g of solid. Flash chromatography using 10% ethyl acetate/dichloromethane as eluent gave 1.0 g of solid. This was combined with 0.5 g of the same compound from a previous reaction and recrystallized from water using decolorizing carbon to give 0.95 g of solid, m.p. 219°-221°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[N:23]=[CH:22][CH:21]=[CH:20][C:13]=1[C:14]([NH:16][CH2:17][C:18]#[CH:19])=[O:15].[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=1)=[N+:25]=[N-:26].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[N:23]=[CH:22][CH:21]=[CH:20][C:13]=1[C:14]([NH:16][CH2:17][C:18]1[N:26]=[N:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=2)[CH:19]=1)=[O:15]
Reactant: C#CCNC(=O)c1cccnc1Nc1cc(OC)ccc1OC
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc(OC)c(Nc2ncccc2C(=O)NCc2cn(Cc3cccc(Oc4ccccc4)c3)nn2)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 78 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,5-dimethoxyaniline (9h, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10h as pure product. To a solution of 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10h, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1h (201 mg, 78%); mp: 154-156° C.; 1H NMR (300 MHz, CDCl3) δ 10.71 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.32 (dd, J=3.0, 1.5 Hz, 1H), 7.76 (dd, J=2.2, 1.5 Hz, 1H), 7.54 (s, 2H), 7.32 (d, J=7.5 Hz, 2H), 7.28 (d, J=2.2 Hz, 1H), 7.18-7.06 (m, 2H), 6.97-6.84 (m, 5H), 6.76 (d, J=8.3 Hz 1H), 6.66-6.62 (m, 1H), 6.42-6.38 (m, 1H) 6.40 (dd, J=3.0 Hz, 1H), 5.45 (s, 2H), 4.66 (d, J=5.2 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 537 [M+H]+. Yield: 78%
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([OH:21])=[CH:17][CH:18]=2)[C:13]1=[O:22])([O:3][CH3:4])=[O:2].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][C:29]([Cl:35])=[CH:30][CH:31]=2)[N:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:35][C:29]1[CH:28]=[C:27]2[C:32]([CH:33]=[CH:34][C:25]([CH2:24][O:21][C:16]3[CH:15]=[C:14]4[C:19]([CH2:20][CH:12]([CH2:11][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[C:1]([O:3][CH3:4])=[O:2])[C:13]4=[O:22])=[CH:18][CH:17]=3)=[N:26]2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccccc1CC1Cc2ccc(O)cc2C1=O
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1CC1Cc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc2C1=O
Yield: 76 %

Procedure:
A mixture of the product of Step 3 (17.5 g, 59 mmol), 2-bromomethyl-7-chloroquinoline (16.65 g, 65 mmol) and K2CO3 (8.97 g, 65 mmol) in acetone (200 ml) was refluxed for 14 hrs. The mixture was filtered and the filtrate was concentrated in vacuo. Chromatography of the resulting crude product on silica gel (eluted with 30% EtOAc/hexane) gave 21.15 g(80%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([N:11]([C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CN(C(=O)Nc1ccccc1)[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]isoquinoline from Example 105, Part A (28 mg, 0.1 mmol) in 1 mL of methylene chloride was added triethylamine (0.015 mL, 0.11 mmol) and phenylisocyanate (0.012 mL, 0.11 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solution was concentrated and purified (ISCO, elution with 0-5% methanol/methylene chloride) to afford 23 mg of the title compound of Example 109 as a white solid. 1H NMR (CDCl3): δ 7.40-7.22 (m, 9H), 7.19-7.15 (m, 1H), 7.14-7.10 (m, 1H), 7.07-7.02 (m, 1H), 6.92-6.88 (m, 1H), 6.28 (s, 1H), 5.19 and 4.22 (ABq, 2H), 3.92 (ABq, 2H), 3.56-3.50 (m, 1H), 3.48-3.40 (m, 2H), 3.33-3.27 (m, 1H), 3.13 (app t, 1H), 3.02 (app t, 1H), 2.35 (s, 3H). LRMS (ESI): 398.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1.I[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:7]=1
Reactant: ICC1CC1
Reactant: CC(C)(C)OC(=O)Cn1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C)(C)OC(=O)C(CC1CC1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
349 mg (0.91 mmol) of tert-butyl [5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate and 216 mg (1.18 mmol) of (iodomethyl)cyclopropane were reacted according to General Method 7A. Yield: 245 mg (62% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24](C(OC(C)(C)C)=O)[N:23]=2)[CH:9]=1)[C:5]#[N:6].CN(C=O)C.Cl>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: CC(C)(C)OC(=O)n1nc(Cn2ncc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2cnn3Cc2n[nH]c3ncccc23)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A jacketed reaction vessel (30 L) equipped with a thermocouple was charged with 3-chloro-5-{[5-chloro-1-(1-t-butyloxycarbonyl-1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-indazol-4-yl]oxy}benzonitrile (1.338 kg; 2.499 moles; 1.0 eq.) and then with DMF (10.7 L) and IPA (2.68 L). Concentrated HCl (2.68 L) was then charged to the vessel during which time the internal temperature rose from 16° C. to 44° C. The mixture was then heated to 60° C. After 1 hour at 60° C., the suspension became a clear solution. Conversion was complete after 1.75 hours as determined by HPLC, at which point the reaction mixture was transferred into a 4-necked round bottom flask (75 L) at 55° C.-60° C. via an in-line filter. The reaction vessel was rinsed with IPA (2 L×2), and the rinse transferred to the flask via the in-line filter. Filtered water (16 L) was then added to the mixture via an additional funnel while maintaining the temperature at 55° C.-60° C., during which crystallization of the title product began. Upon completion of the water addition, the mixture was stirred at 55° C. for 40 minutes, then cooled to room temperature and filtered with a filter pot. The wet cake was rinsed with filtered IPA:water (3:7, 10 L), and then with filtered water (7 L×6), and then dried in a vacuum oven at 40° C. for two days to afford the title product.
Reaction SMILES: [SH2:1].[NH2:2][C:3]([CH:9]([CH3:11])[CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6]>N1C=CC=CC=1>[NH2:2][C:3]([CH:9]([CH3:11])[CH3:10])=[C:4]([C:7]#[N:8])[C:5](=[S:1])[NH2:6]
Reactant: S
Reactant: CC(C)C(N)=C(C#N)C#N
Solvent: c1ccncc1
Product: CC(C)C(N)=C(C#N)C(N)=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
While maintaining the temperature below 45°, hydrogen sulfide gas was passed for 2 hours into a stirred solution of 122.0 g of 3-amino-2-cyano-4-methyl-2-pentenenitrile and 91.5 g of triethylamino in 122 ml of pyridine. The mixture was stirred for 1 hour at room temperature, then was poured over 2 liters of ice. Th solid was collected, washed with water, dried and recrystallized from ethanol-water to give 128.3 g 3-amino-2-cyano-4-methyl-2-pentenethioamide, mp 112°-114°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.Cl.[CH3:31][C:32]1[CH:41]=[C:40]([CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>CN(C)C=O>[CH3:31][C:32]1[CH:41]=[C:40]([CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([S:50]([NH:1][C@H:2]3[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:52])=[O:51])=[CH:46][CH:45]=2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To the stirred solution of 687 mg (2.4 mol) of di-tert-butyl cis-4-aminopyrrolidine-1,3-dicarboxylate (prepared according to J. Med. Chem. 2001, 44, 1192-1201) was added 2.1 mL of Hunig's base in 10 mL of N,N-dimethylformamide and 922 mg of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride. The solution was stirred at room temperature overnight. The N,N-dimethylformamide was removed in vacuo, and the residue was dissolved in 100 mL of chloroform. The chloroform solution was washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified using flash chromatography on silica gel eluting with ethyl acetate/hexane to provide 929 mg (65% yield) of di-tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1,3-dicarboxylate. MS: 598.4 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12]Br.C(#N)C>C(Cl)Cl>[Cl:10][CH2:11][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: ClCCBr
Reactant: c1ccc2c(c1)CCN2
Solvent: ClCCl
Solvent: CC#N
Product: ClCCN1CCc2ccccc21

Procedure:
A microwave vial was charged with indoline (0.5 g, 4.19 mmol), 2-chloro-1-bromoethane (0.502 ml, 6.25 mmol), TEA (0.7 ml, 6.25 mmol) and acetonitrile (10 ml). The vial was irradiated with microwaves for 1 hour at 80° C. The mixture was diluted with DCM and washed with water (1×10 ml). The organic layer was dried and concentrated and the residue was purified by flash column chromatography (silica, Hexane/EtOAc 95:5 to 0:1). The product was isolated as a violet solid (400 mg; 52%).
Reaction SMILES: [C:1]([C:9]1[CH:21]=[CH:20][C:12]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])(O)=O.[Na+].CI>CN(C=O)C>[CH3:22][N:13]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]1[CH:20]=[CH:21][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)CCCNc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CCCC(=O)O)c1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1.41 g (0.05 mole) of 4-(4-benzoylanilino)butyric acid are dissolved in 15 ml of DMF, and 0.84 g of NaHCO3 (0.01 mole) and 1.42 g (0.01 mole) of methyl iodide are added, and the mixture is stirred at 80° C. for about 3 h. It is then poured onto ice-water, the mixture is extracted with ethyl acetate, the organic phase is dried with MgSO4, and the solvent is evaporated off in vacuo. The residue is chromatographed on silica gel using n-hexane/ethyl acetate as eluent. The oily product is immediately hydrolyzed with 2 N LiOH. The title compound is obtained and has the melting point 111°-113° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH:14]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:15]=1.C([B-](F)(F)F)=C.[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)=[CH2:15]
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: C=C[B-](F)(F)F
Agent: CC(=O)[O-]
Solvent: CCCO
Product: C=Cc1ccc(C(C)(C)C(=O)O)cc1
Yield: 598.4 %

Procedure:
2-(4-Bromophenyl)-2-methylpropanoic acid (30 g), PPh3 (5.0 g), potassium vinyltrifluoroborate (24.8 g), potassium carbonate (51.2 g), and palladium acetate (1.43 g) were dissolved in 1-propanol (198 ml) and distilled water (99 ml). After deaeration, the mixture was stirred under reflux for 6 hrs under nitrogen atmosphere. Insoluble matters were removed by filtration and washed with 1-propanol (210 ml). The filtrate was then concentrated under reduced pressure. Concentrated residues were partitioned between CPME (300 ml) and distilled water (150 ml, comprising 4.17 ml of ethylenediamine). The organic layer was removed and the aqueous layer was adjusted to pH 5 by using 2 N hydrochloric acid. The aqueous layer was extracted with a mixture of isopropyl acetate (240 ml) and heptane (240 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethanol (300 ml) was added thereto for suspending and washing the resultant. The solid was removed by Celite filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (21.7 g, 93%).
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([C:13]([O:15]CC)=O)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[C:10]([C:13]([NH:31][CH2:30][CH2:29][C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)[NH:25][CH:24]=2)=[O:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc(Cc2ccccc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccccc2)n1
Yield: 43.8 %

Procedure:
This compound was prepared according to method F with ethyl 5-benzyl-1,2,4-oxadiazole-3-carboxylate (0.1 g; 0.432 mmol) in methanol (6 mL) and sodium hydroxide in water (2M, 6 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.432 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (6 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.072 g (44%) of 5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[Cl:15])=[O:10].[NH:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:31]([C:33](O)=[O:34])[CH3:32].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:30]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[C@H:31]([C:33]([NH:2][C@H:3]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[Cl:15])=[O:10])=[O:34])[CH3:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
At 0° C. the solution of 88 mg (0.2 mmol) of HCl.Lys(ClZ)-OBzl in 5 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 38 mg (0.2 mmol) of Boc-Ala-OH, 30 mg (0.22 mmol) of 1-hydroxybenzotriazole and 45 mg (0.22 mmol) of dicyclohexylcarbodiimide in 5 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 5 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of Boc-Ala-OH. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 20 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (30 ml×3), saturated NaCl in water (30 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 112 mg (98%) of the title compound as a colorless powder. Mp94–96° C., FAB-MS (m/e) 575[M+H]+, 475[M-Boc]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2=[O:27])[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(ethyloxy)ethanamine using methods similar to Example 563 to provide a white solid: 1H NMR (CDCl3) δ 10.36 (1H, b), 8.53 (1H, s), 8.16 (1H, s), 7.37 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.37 (2H, t, J=6 Hz), 4.13 (2H, s), 3.42-3.50 (8H, m), 3.24 (2H, t, J=6 Hz), 1.99 (2H, t, J=6 Hz), 1.48-1.62 (4H, m), 1.10 (3H, t, J=7 Hz); ES+ MS: 511 (M+H+).