Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:6]1([CH2:5][C:4]2[CH:3]=[C:2]([CH:14]=[CH:13][CH:12]=2)[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: N#CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCCCCCOc1cccc(CN2CCCCC2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(3-Hydroxybenzyl)piperidine (9.55 g) was heated with 6-bromohexanenitrile (10.2 g) and potassium carbonate (13.8 g) under reflux in acetone (150 ml) for 66 hours. The reaction mixture was cooled and filtered. The solvent was removed by evaporation and the residue was heated with stirring at 100° C. for one hour to remove unreacted 6-bromohexanenitrile and to yield 6-(3-piperidinomethylphenoxy)hexanenitrile as an oil.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:10][OH:11])[CH2:4][CH3:5])[CH3:2].[CH3:22][N:23]=[C:24]=[O:25]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:22][NH:23][C:24](=[O:25])[O:11][CH2:10][C:9]1[C:12]([CH3:18])=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: CN=C=O
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(CO)c1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(COC(=O)NC)c1[N+](=O)[O-]
Yield: 91.6 %

Procedure:
A mixture of 3-[(1-ethylpropyl)amino]-6-methyl-2,4-dinitrobenzyl alcohol (1.0 g; 0.0033 mol), methyl isocyanate (used in excess over theory), triethylamine (1 drop) and benzene (10 ml) is refluxed for 2 hours. The precipitated solid is collected to afford 1.1 g (91.6%) title product, melting point 117°-120° C.
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Cl[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1>C(COC)OC>[CH3:14][C:12]1[CH:13]=[C:8]([Sn:3]([CH3:5])([CH3:4])[CH3:2])[CH:9]=[C:10]([CH3:15])[N:11]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1cc(Cl)cc(C)n1
Agent: [Na]
Solvent: COCCOC
Product: Cc1cc([Sn](C)(C)C)cc(C)n1
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
To a mixture of 100 g sodium (30% dispersion in toluene) and 400 ml dimethoxyethane (DME) cooled in an ice-salt bath and under nitrogen was added a solution of 121 g trimethyltin chloride in 50 ml DME over a 2 hour period while keeping the temperature below 5° C. The mixture was stirred at 0°-5° C. for 2.5 hours and then 70 g 4-chloro-2,6-dimethylpyridine in 50 ml DME was added over a 1.5 hour period while keeping the temperature at 0°-10° C. The reaction mixture was stirred at the latter temperature for 1 hour and then allowed to stand at room temperature overnight. The mixture was filtered and concentrated, and the residue treated with ether and again filtered and concentrated. The resulting orange liquid was distilled, collecting the material boiling at 130° C. (20 mm.) to give 80 g 2,6-dimethyl-4-(trimethylstannyl)pyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[O:21]1[CH2:26][CH2:25][O:24][C:23]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:22]1=2.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:3][C:2]([C:28]2[CH:29]=[CH:30][C:22]3[O:21][CH2:26][CH2:25][O:24][C:23]=3[CH:27]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4c(c3)OCCO4)cnc2Cl)cc1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
A 15 mL sealed pressure tube was charged with N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (190 mg, 0.503 mmol), 2,3-dihydrobenzo[b][1,4]dioxin-6-ylboronic acid (100 mg, 0.553 mmol) in EtOH (1.5 ml). Pd(PPh3)4 (29 mg, 0.025 mmol) was added, followed by sodium carbonate (2M, 0.629 mL). The tube was purged with argon, backfilled with argon, sealed and stirred at 85° C. for 1.5 hours. The crude was partitioned between water and methylene chloride and extracted with methylene chloride (3×, 10 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The solid was purified by ISCO with a 20-50% gradient of EtOAc in hexanes to afford desired product. MS (ESI pos. ion) m/z calcd for C20H12ClN2O5S: 432.8; found 433.3 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83 (s, 3 H), 4.30 (s, 4 H), 6.99 (d, J=8.3 Hz, 1 H), 7.06-7.15 (m, 4 H), 7.61-7.72 (m, 2 H), 7.78 (d, J=2.3 Hz, 1 H), 8.47 (s, 1 H), 10.21 (s, 1 H).
Reaction SMILES: C([O:3][C:4](=O)[C:5](OCC)=[CH:6][NH2:7])C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][NH:16][NH2:17]>>[NH2:7][C:6]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[Cl:12])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccccc1Cl
Reactant: CCOC(=O)C(=CN)OCC
Product: Nc1cc(=O)n(Cc2ccccc2Cl)[nH]1
Yield: 40 %

Procedure:
35 g of β-amino--ethoxyacrylic acid ethyl ester and 32 g of 2-chlorobenzylhydrazine when reacted as described in Example 45 yield 17.5 g of the compound identified above as colorless crystals of melting point 153°. (Yield: 40% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:18][C:10]1[N:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: [O-][n+]1cccc(Oc2ccc(Cl)cc2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(Oc2ccc(Cl)nc2)cc1

Procedure:
A solution of 22 g of 3-(p-chlorophenoxy)pyridine N-oxide in 500 ml of chloroform is added dropwise to 77 g of refluxing phosphorous oxychloride. The mixture is refluxed 30 minutes, cooled and concentrated at reduced pressure. The resulting oil is dissolved in 400 ml of dichloromethane, washed with 40 ml ice cold concentrated ammonium hydroxide and the dichloromethane solution is dried over anhydrous MgSO4. The mixture is filtered, concentrated under reduced pressure and distilled to yield the mixture of desired chlorinated pyridines; bp 103°-105° C./0.1 mm. The oil is dissolved in 100 ml of toluene and chromatographed over 400 g of silica gel in toluene to yield in the first eluate, 6-chloro-3-(p-chlorophenoxy)pyridine. Continued elution with toluene yields 2-chloro 3-(p-chlorophenoxy)pyridine. Finally, elution with toluene-methanol (50:50) yields 4-chloro-3-(p-chlorophenoxy)pyridine.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+].Cl>ClCCl.CO>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CON=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CONCc1ccc(F)cc1
Reaction time: 96 h
Yield: 40.9 %

Procedure:
A solution of 4-fluorobenzaldehyde-O-methyloxime (93.2 mmol) in dichloromethane (150 ml) was treated with sodium cyanoborohydride (9.18 g, 0.146 mol) followed by 120 ml of 2 N hydrochloric acid in methanol added dropwise over 30 minutes. After 96 h at 22° C., the solvent was evaporated under reduced pressure, the residue was slurried with water and adjusted to pH 9 with 2 N aqueous sodium hydroxide. The aqueous phase was extracted twice with dichloromethane and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual oil was chromatographed on silica gel (elution, toluene-ethyl acetate 0-10%) and gave 5.92 g (41% yield) of the title amine as a clear oil. 1H NMR 400 MHz (CDCl3) δ (ppm): 3.49 (3H, s), 4.01 (2H, s), 5.69 (1H, broad s), 7.01 (2H, m), 7.31 (2H, m). The hydrochloride salt was obtained as a white solid: mp 170-171° C. Anal. calcd for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.31; H, 5.80; N, 7.26
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=O)[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.CN(C=O)C.[Br:20]N1C(=O)CCC1=O>ClCCl>[NH2:12][C:7]1[C:8]([C:9]([O:10][CH3:11])=[O:14])=[C:3]([O:2][CH3:1])[C:4]([Br:20])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc(Br)c1OC

Procedure:
A mixture of Example 470A (9.8 g, 50.7 mmol), DMF (50 mL), and dichloromethane (150 mL) was cooled to 0° C., treated portionwise with N-bromosuccinimide (12.6 g, 76 mmol), stirred until all the starting material was consumed, and filtered. The filter cake was washed with dichloromethane combined filtrates were concentrated, treated with anhydrous methanol (450 mL), and heated to reflux for 54 hours. Purification by flash column chromatography on silica gel with 15% ethyl acetate/hexanes provided the desired product. MS (ESI(+)) m/e 260, 262 (M+H)+, 277, 279 (M+NH4)+, 282, 284 (M+Na)+; (ESI(−)) m/e 258, 260 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.34 (d, 1H), 6.50 (d, 1H), 5.63 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([S:15](Cl)(=[O:17])=[O:16])[C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[OH-].[NH4+:20]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([S:15](=[O:17])(=[O:16])[NH2:20])[C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(Cl)c(S(=O)(=O)Cl)c2C1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=O)N1CCc2ccc(Cl)c(S(N)(=O)=O)c2C1

Procedure:
2-Acetyl-8-amino-7-chloro-1,2,3,4-tetrahydroisoquinoline (0.04 mole) in concentrated hydrochloric acid (8.4 ml.) is cooled to 3° C. and treated with sodium nitrite (0.044 mole) dissolved in water (6 ml.). After stirring for 30 minutes, the reaction is tested for nitrous acid with starch/iodide paper. If the test for nitrous acid is negative, more sodium nitrite is added in small portions with stirring over a period of time until the test is positive. When a positive reaction is obtained, magnesium chloride (0.032 mole) is added and the resulting mixture is added to a mixture of acetic acid (40 ml.) saturated with sulfur dioxide and cuprous chloride dihydrate (0.0129 mole) maintained at 30° C and stirred. After about 30 minutes, the mixture is diluted with water (60 ml.) and extracted with ether. The extract is then washed with dilute aqueous sodium bicarbonate/sodium carbonate solution at pH 8-9, then with water, and dried over sodium sulfate. The ether is evaporated to yield 2-acetyl-8-chlorosulfonyl- 7-chloro-1,2,3,4-tetrahydroisoquinoline. 2-Acetyl-8-chlorosulfonyl-7-chloro-1,2,3,4-tetrahydroisoquinoline (0.022 mole) is treated with concentrated ammonium hydroxide (30 ml.) with cooling. The resulting solid is filtered off and washed with water to give 2-acetyl-7-chloro-8-sulfamyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][C:44]([NH2:47])([CH3:46])[CH3:45]>>[C:44]([NH:47][C:28]([C:25]1[C:24]2[CH:33]=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:21]([N:35]3[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]3)=[C:22]([F:34])[C:23]=2[O:27][N:26]=1)=[O:30])([CH3:46])([CH3:45])[CH3:43]
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: CC(C)(C)N
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NC(C)(C)C)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 2-methylpropan-2-amine
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>CN(C)C=O>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Reactant: BrCCCCCCOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)(CCCCCCOCc1ccccc1)C(=O)OCC
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
First, 1.5 g of 60% sodium hydride and 30 ml of dry dimethylformamide were placed in a 200 ml flask. Then, 30 ml of a dimethylformamide solution containing 11.5 g of diethyl 2-(6-benzyloxyhexyl)malonate was added dropwise to the reaction mixture under ice water cooling, and the resultant reaction mixture was stirred at room temperature for 1 hour and at 130° C. for 30 minutes. Then, 30 ml of a dimethylformamide solution containing 10 g of 1-bromo-6-benzyloxyhexane was added dropwise to the reaction mixture, and the resultant reaction mixture was stirred for 3 hours. The reaction mixture was poured into diluted hydrochloric acid, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 14.8 g of diethyl 2,2-bis(6-benzyloxyhexyl)malonate (Y: 91.5%). The compound thus obtained had a purity of 94.7% by GC.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C@H:21]3[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:22])[N:14]([CH2:23][CH2:24]Br)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C@H:21]3[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:22])[N:14]([CH2:23][CH2:24][N:26]3[CH:30]=[CH:29][N:28]=[CH:27]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(CCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: CO
Product: COc1ccc(C2=NN(CCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
A solution of 2 g of compound 112 and 3 g of imidazole in methanol was left for 18 h at room temperature. After evaporating the solvent, the residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was dissolved in ethyl acetate and filtered over silica. The compound crystallized as the hydrochloride from tetrahydrofuran. M.p. 198°-199° C.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:29])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:28]3[CH2:27][O:26][CH2:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:29])[NH2:5])=[CH:18][CH:17]=3)[C:28]=2[CH2:27][O:26]1
Reactant: C[C@H](C(=O)Nc1ccc(Oc2cccc3c2COC3)cc1)N(C(=O)[O-])C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2COC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A solution of 1,1-dimethylethyl((1R)-2-{[4-(1,3-dihydro-2-benzofuran-4-yloxy)phenyl]amino}-1-methyl-2-oxoethyl)carbamate (Intermediate 6, 108 mg) and TFA (1 ml) in dichloromethane (4 ml) was stirred under argon at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by SCX to afford the title compound (81 mg).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7](F)[CH:6]=1)([F:4])[F:3].C(=O)([O-])[O-].[K+].[K+].[C:20]([C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)#[N:21].O>CN(C=O)C>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([C:2]([F:4])([F:3])[F:1])=[CH:6][C:7]=1[O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:20]#[N:21])=[O:10]
Reactant: N#Cc1cccc(O)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2C=O)c1
Temperature: 110 °C

Procedure:
A mixture of 4-(1,1,1-trifluoromethyl)-2-fluoro-benzaldehyde (2.5 g), potassium carbonate (1.79 g) and 3-cyanophenol (1.54 g) in DMF (20 ml) was heated at 110° C. for 2 h then cooled. Water (200 ml) was added and the mixture extracted with ethyl acetate, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 2:1 to give a colourless oil, yield 2.0 g.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1([CH3:28])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][N:21]=3)[CH:9]=[CH:8][C:7]1=2>CCOCC>[CH3:5][C:6]1([CH3:28])[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]2[CH:11]=[C:10]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([OH:27])[CH2:1][CH3:2])=[CH:22][N:21]=3)[CH:9]=[CH:8][C:7]1=2
Reactant: CC[Mg]Br
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cn3)ccc21
Solvent: CCOCC
Product: CCC(O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Reaction time: 1 h

Procedure:
Four ml of a 3M (12 mmol) solution of ethylmagnesium bromide in ether is placed in a 3-necked flask fitted with a mechanical stirrer, a reflux condenser protected by a drying tube and a pressure-equalizing dropping funnel protected by a drying tube. The flask is cooled in an ice-bath and a solution of 3.174 g (10 mmol) of 2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]pyridine-5-carboxaldehyde in 10 ml of dry ether is added slowly with vigorous stirring. The cooling bath is then removed and the mixture heated at reflux for 3 hours. The mixture is then cooled in an ice-salt bath and 5 ml of saturated ammonium chloride solution is added. The mixture is stirred for a further 1 hour and then filtered and the residue washed with two 10 ml portions of ether. The ether solution is then separated, dried (MgSO4) and the ether removed in vacuo. The residue is then purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][SH:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[N+:25](/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-:27])=[O:26]>C(#N)C>[C:10]([O:14][C:15]([NH:17][C@@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][S:20][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][N+:25]([O-:27])=[O:26])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)[C@@H](CS)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H](CSC(C[N+](=O)[O-])c1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Diisopropylethylamine (3.38 mL, 19.4 mmol) was added to a solution of methyl N-(tert-butoxycarbonyl)-D-cysteinate (3.04 g, 12.9 mmol) and □-trans-nitrostyrene (1.93 g, 12.92 mmol) in acetonitrile (80 mL). After 15 min, the reaction was concentrated. Purification by silica gel chromatography (100% hexanes→30% ethyl acetate/hexanes) gave the title compound (4.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[C:26]([CH3:33])[CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:32])=[C:26]([CH3:33])[CH:25]=1
Reactant: Cc1cc(Cl)ccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4C)cc3)c2cc1OC
Yield: 80.1 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (55 mg) was dissolved in toluene (5 ml) with heat, 4-chloro-2-methylphenyl isocyanate (90 mg) was added, and the admixture was refluxed with heat for 26 minutes. The separated crystals were filtered and then washed with toluene to obtain 69 mg of the title compound (yield: 80%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[S:11][C:10]=1C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Cu].N1C2C(=CC=CC=2)C=CC=1>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[S:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)c1cc(OCc2ccccc2)cs1
Temperature: 150 °C
Yield: 70.5 %

Procedure:
A mixture of 1F (14.5 g) and quinoline (50 ml) was treated with copper powder (4.57 g) and heated to 150 ° C. The reaction mixture is heated for 25 minutes at 150° C. and cooled to room temperature. The mixture was filtered and washed with water. Aqueous quinoline was acidified with 6N HCl (pH=2) and extracted with diethyl ether twice. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue was chromatographed to yield a yellow liquid (8.74 g, 71%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]1[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1
Reactant: CCOC(=O)Cn1c(-c2ccccc2Cl)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccccc2Cl)nc2cccnc21

Procedure:
A mixture of 9.7 g (0.0308 mole) of 2-(2-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester, 2.5 g (0.0339 mole) of sodium hydroxide (pellets), and 100 ml of ethanol-water (1:1) was refluxed for 1 hr. The ethanol was evaporated and the residual aqueous solution was extracted with methylene chloride (2×30 ml). The aqueous layer was acidified with concentrated hydrochloric acid and filtered. The filter cake was recrystallized from ethanol-water to give 7.0 g (79%). A 2.0-g portion was recrystallized from ethanol-isopropyl ether to give white needles, mp 227°-228° C.
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1.O>O1CCCC1>[CH2:1]([O:5][C:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][S:11][N:10]=1)[C:2]#[C:3][CH3:4]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-butyn-1-ol (530 mg, 7.5 mmol) and sodiumhydride (180 mg, 7.5 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.