Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[CH2:12][OH:13])[CH:7]=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:20])[CH2:18]C.Cl>CN(C)P(N(C)C)(N(C)C)=O>[OH:10][C:9]1[CH:8]=[CH:7][C:6]([CH:11]([CH3:14])[CH2:12][OH:13])=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][O:20][CH2:17][CH3:18]
Reactant: CCOC(=O)CC
Reactant: CC(=O)c1cc(C(C)CO)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOCC(=O)c1cc(C(C)CO)ccc1O
Reaction time: 2 h

Procedure:
2-(3-Acetyl-4-hydroxyphenyl)propan-1-ol (15.0 g; 0.077 mol) was dissolved in hexamethylphosphoramide (150 ml) and slowly added to a stirred slurry of sodium hydride (10.0 g; 0.417 mol) in hexamethylphosphoramide (40 ml) at a rate sufficient to maintain the temperature below 25° C. Ethyl propionate (20.0 g; 0.2 mol) was added and the mixture stirred for 2 hours before pouring into 2N hydrochloric acid (600 ml). The solution was extracted with ether (2×300 ml) and the extracts evaporated to give 2-[4-hydroxy-3-(3-oxapentanoyl)phenyl]propan-1-ol as a yellow oil. This was dissolved in ethanol (100 ml) containing concentrated hydrochloric acid (20 ml) and the solution was refluxed for 30 mins. The ethanol was removed in vacuo and the aqueous phase extracted with chloroform (2×150 ml). The combined extracts were washed with saturated sodium bicarbonate solution and dried over magnesium sulphate. The solvent was removed and the resulting oil was chromatographed on a silica gel column using ether as eluent. Recrystallisation of the product using hexane/ether (2:1) furnished a white microcrystalline solid (5.0 g) mp 59.5°-60.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:3]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:42]([O:46][CH2:47][CH3:48])(=[O:45])[CH:43]=[CH2:44]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:4]1[CH:3]=[C:2](/[CH:44]=[CH:43]/[C:42]([O:46][CH2:47][CH3:48])=[O:45])[CH:7]=[CH:6][CH:5]=1
Reactant: COCOCc1cccc(Br)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(COCOC)c1

Procedure:
Under a nitrogen atmosphere, a crude product of 1-bromo-3-((methoxymethoxy)methyl)benzene (3.60 g), triethylamine (6.50 mL), palladium acetate (175 mg), tri-o-tolylphosphine (711 mg) and ethyl acrylate (8.4 mL) were stirred in DMF (30 mL) at 110° C. for 1 hr. The solvent of the reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.41 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:15]3)C3C(=CC=CC=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:43]([NH2:46])[CH2:44][CH3:45]>>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:46][CH2:43][CH2:44][CH3:45])=[O:41])[CH2:15]3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Reactant: CCCN
Product: CCCNC(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Yield: 93 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]pentanoic acid (0.09 g, 0.16 mmol) prepared in Example 128 and n-propylamine (52 μl), the same procedure as shown in Example 129 was repeated to give the titled compound (0.09 g, overall yield: 93%) as a white powder (cis:trans=5:2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:13][CH2:12][Br:11])([O-:3])=[O:2]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1cccc(OCCCBr)c1
Yield: 94.7 %

Procedure:
13.9 g of 3-nitrophenol, 101 g of 1,3-dibromopropane and 15.2 g of anhydrous potassium carbonate were reacted in 100 ml of methyl ethyl ketone for 2 hours by heating under reflux. After completion of the reaction, insoubles were removed from the reaction mixture by filtration, and the filtrate was then concentrated. Next, the resultant concentrate was dissolved in 300 ml of chloroform, and this chloroform solution was further washed with water. Afterward, the washed organic layer was dried over anhydrous magnesium sulfate and then treated with under reduced pressure to distill off the solvent, thereby obtaining 24.6 g of 3-(3-nitrophenoxy)propyl bromide (Compound d) in an oily state. This was used for a subsequent reaction without purifying.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C(O)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:21][CH:18]1[CH2:20][CH2:19]1)#[N:2]
Reactant: NC1CC1
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CCO
Product: N#CN=C(NC1CC1)NC1CCCc2ccccc21
Reaction time: 120 h

Procedure:
A solution of 24.6 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 25.0 g of cyclopropylamine in 250 ml of ethanol was heated at reflux with stirring for ca. 120 hours. The solvent was then removed by evaporation in vacuo. The residual oil was dissolved in a mixture of hot isopropyl acetate and ethanol, and the solution was allowed to stand in the refrigerator overnight to give the partially-purified product as a white, crystalline solid. A further quantity of the crude product was obtained by the concentration and subsequent cooling of the mother liquor. Recrystallization from isopropyl acetate, containing a small amount of ethanol, gave N"-cyano-N-cyclopropyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as 7.75 g of a white, crystalline solid, mp 170.5°-171.5° C.
Reaction SMILES: [CH2:1]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39](O)[CH:40]([OH:46])[CH2:41][CH2:42][CH2:43][CH2:44][OH:45].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:19]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[O:46][CH:40]([CH2:41][CH2:42][CH2:43][CH2:44][OH:45])[CH2:39][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: OCCCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCCC1(CCCCCCCC/C=C\C/C=C\CCCCC)OCC(CCCCO)O1
Temperature: 25 °C

Procedure:
A mixture of dilinoleyl ketone (I, previously prepared as described in Example 1, 1.05 g, 2.0 mmol), 1,2,6-hexanetriol (0.54 g, 4 mmol) and pyridinium p-toluenesulfonate (100 mg, 0.4 mmol) in 150 mL of toluene was refluxed under nitrogen overnight with a Dean-Stark tube to remove water. The resulting mixture was cooled to room temperature. The organic phase was washed with water (2×60 mL), brine (60 mL), and dried over anhydrous Na2SO4. Evaporation of the solvent resulted in a yellowish oily residual (1.5 g). The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with 0-0.5% methanol in dichloromethane as eluent. This afforded 1.4 g of pure II as colourless oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([N-]C(C)C)([CH3:25])[CH3:24].[Li+].C(Br)C=C>C1COCC1>[CH2:25]([C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])[CH:23]=[CH2:24]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of dimethyl 2-(4-phenoxyphenyl)malonate (2.56 g, 8.54 mmol) in dry THF (50 mL) was cooled to −78° C. and then lithium diisopropylamide (4.7 mL of a 2M solution in ThF, 9.8 mmol) was added. The reaction was stirred at −78° C. for 1 hour and then allyl bromide (11.4 mg, 9.4 mmol) was added. The reaction was stirred at −78° C. for 3 hours and then allowed to warm to room temperature and heated in a 75° C. oil bath until the reaction was shown to be complete by TLC. The reaction was cooled to room temperature and quenched with 1N HCl. Extraction with ether and drying of the ether extracts (MgSO4) gave crude product. Purification by filtration through silica gel 60 (70-230 mesh) using EtOAc, followed by HPLC (porasil) using 11% EtOAc/hexanes gave 1.8 g of dimethyl 2-(2-propenyl)-2-(4-phenoxyphenyl)malonate as a viscous oil: 1H NMR (200 mHz, CDCl3) δ 7.4-6.85 (9H, m), 5.75 (1H, m), 5.05 (2H, m), 3.75 (6H, s), 3.1 (2H, d).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](O)=[O:26]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1ccco1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1ccco1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 2-furancarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 82% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Cl)c1ccccc1

Procedure:
2-chloro-5-nitroaniline (Aldrich), (10.0 mmol) was used in general procedure 1 with benzoyl chloride (12.2 mmol). The product was purified by silica gel chromatography (40% EtOAc/Hex) to give N-(2-chloro-5-nitrophenyl)benzamide as a tan solid. MS (Q1) 276.1 (M)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC>CN(C=O)C.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>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccccn3)c2s1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a stirred solution of viii (110 g, 0.27 mol) in DMF (1.1 L) was added 2-tributylstannyl pyridine (298 g, 0.81 mol). The resulting solution was purged with N2 for 15-20 min followed by addition of Pd(PPh3)4 (25.41 g, 0.022 mol). The resulting reaction mixture was heated to 100° C. under N2 atmosphere for 15-16 h. The reaction was cooled to 40-45° C. and filtered through celite. The celite was washed with DMF (500 mL) and hot EtOAc (1.50 L) and the combined filtrate concentrated at 60-70° C. in vacuo. The residue was purified through silica (20% EtOAc-Hexanes to 100% EtOAc) to obtain ix (76 g, 70%). 1H-NMR (DMSO-d6, 400 MHz): δ 1.08 (t, J=7.20 Hz, 3H), 3.19 (q, J=6.80 Hz, 2H), 5.26 (s, 2H), 6.84 (br s, 1H), 7.32-7.43 (m, 5H), 7.51 (d, J=7.20 Hz, 2H), 7.69 (d, J=2.0 Hz, 1H), 7.95 (m, 1H), 8.25 (m, 1H), 8.78 (m, 1H) and 10.46 (br s, 1H). MS: 405.30 [M+H]+.
Reaction SMILES: O.NN.[CH:4]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5]1.[OH-].[K+]>O>[CH:4]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)C(=O)c1ccc(SC2CC2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Hydrazine hydrate (14.19 g, 283.5 mmol) was cooled to −50° C. and (4-cyclopropylsulfanylphenyl)oxoacetic acid (Preparation 1, 12.6 g, 56.7 mmol) added in one portion. The vigorously-stirred slurry was warmed firstly to room temperature and then at 80° C. for 5 min. Solid KOH (8.76 g, 156.5 mmol) was added in four equal portions and the resulting solution heated at 100° C. for 20 h. On cooling to room temperature, water (25 ml) was added and the aqueous phase washed with Et2O (20 ml). The ethereal phase was itself washed with water (2×15 ml) and sufficient concentrated HCl added to the combined aqueous phases to adjust the pH to 1. The resulting precipitate was then extracted into EtOAc (2×300 ml) and the combined organic phases washed with water (3×100 ml), brine (200 ml) then dried (MgSO4). Evaporation of the solvent afforded the title compound: m/z (ES−)=207.1 [M−H+]−.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:21][CH2:22][C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)=[CH:6][C:7]([F:20])=[C:8]([CH:19]=1)[C:9]([NH:11][S:12]([N:15]1[CH2:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])=[O:10])(=[O:3])[CH3:2].[CH3:33][Mg]Br.Cl>O1CCCC1.C(OCC)(=O)C>[C:23]12([CH2:22][O:21][C:5]3[C:4]([C:1]([OH:3])([CH3:33])[CH3:2])=[CH:19][C:8]([C:9]([NH:11][S:12]([N:15]4[CH2:18][CH2:17][CH2:16]4)(=[O:14])=[O:13])=[O:10])=[C:7]([F:20])[CH:6]=3)[CH2:24][CH:25]3[CH2:26][CH:27]([CH2:28][CH:29]([CH2:31]3)[CH2:30]1)[CH2:32]2
Reactant: CC(=O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a solution of 5-acetyl-4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluorobenzamide (0.200 g, 0.43 mmol) in anhydrous tetrahydrofuran (4 mL) was added methylmagnesium bromide (3.0 M solution in diethyl ether, 0.29 mL, 0.86 mmol) at −78° C. After 1 hour at −78° C., additional methylmagnesium bromide (3.0 M solution in diethyl ether, 0.29 mL, 0.86 mmol) was added; the reaction mixture was allowed to warm to ambient temperature, and stirred for 1 hour. After addition of 1 N hydrochloride acid (5 mL) and diluting the mixture with ethyl acetate (100 mL), the organic phase was washed with brine (5 mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave a residue which was purified by reverse-phase preparative HPLC to give the title compound as a colorless solid (0.101 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 11.63 (br s, 1H), 7.93 (d, J=9.0 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 5.25 (s, 1H), 4.04 (t, J=7.6 Hz, 4H), 3.65 (s, 2H), 2.22-2.10 (m, 2H), 2.01 (br s, 3H), 1.79-1.61 (m, 12H), 1.51 (s, 6H); 19F NMR (282 MHz, DMSO-d6) δ −111.6 (s, 1F); MS (ES−) m/z 479.2 (M−1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7](Cl)[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH3:21][NH:22][CH3:23]>O.CN(C=O)C>[CH3:21][N:22]([CH3:23])[C:7]1[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N(C)C)cc(C(F)(F)F)nc1C(F)(F)F
Reaction time: 3 h

Procedure:
A mixture of 7.67 g (0.024 mol) of product of Example 19 and 5.4 g (0.048 mol) of 40% solution of dimethylamine in H2O and 50 ml of DMF was stirred for three hours. The temperature rose to 48° C. and dropped back down to room temperature. The reaction mixture was poured into H2O, extracted with ether, washed with diluted HCl, dried (MgSO4) and concentrated in vacuo to 6.63 g of solid which was recrystallized in hot hexane affording 6.01 g (75.8%) of product as a white solid; mp 63.5°-65° C.
Reaction SMILES: [CH:1]12[CH2:15][CH2:14][CH:4]([C:5]3[C:6]4[C:11]([NH:12][C:13]=31)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:3][CH:2]2[N:16](C)[CH:17]=O.[CH2:20](O)C>[OH-].[Na+]>[CH3:17][NH:16][CH:2]1[CH2:3][CH:4]2[CH2:14][CH2:15][CH:1]1[C:13]1[N:12]([CH3:20])[C:11]3[C:6]([C:5]=12)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CCO
Reactant: CN(C=O)C1CC2CCC1c1[nH]c3ccccc3c12
Agent: [Na+]
Agent: [OH-]
Product: CNC1CC2CCC1c1c2c2ccccc2n1C

Procedure:
A solution of N-(2,3,4,9-tetrahydro-1,4-ethano-1H-carbazol-2-yl)-N-methyl-formamide (3.9 g, 0.0145 mole, described in Example 7) in 20 ml of 10% sodium hydroxide and 40 ml ethanol was refluxed under nitrogen on a steam-bath for 5 hr. The solution was evaporated to dryness and the residue was taken up in diethyl ether. The organic layer was washed (3×) with 2 N hydrochloric acid and the acidic layer was washed with diethyl ether. The aqueous layer was made basic with 25% sodium hydroxide and extracted with diethyl ether. The ether extract was washed with water, dried, evaporated to afford the title compound as a pale yellow oil (3 g): NMR (CDCl3) δ 1.0 (s, 1H), 2.32 (3, 3H), 3.75 (s, 3H) and 2.1-7.7 (m, 4H). It was chromatographed on silica gel and eluted with 5% methanol-chloroform to give a pale yellow oil (2.2 g) which was dissolved in dichloromethane and treated with a solution of hydrogen chloride in diethyl ether to form a gummy precipitate. The residue was crystallized from methanol-dichloromethane-diethyl ether to yield a greenishgray compound (2.0 g). Recrystallization from methanol-dichloromethanediethyl ether afforded the hydrochloride salt of the title compound as an off-white powder (1.95 g): mp 204°-205° C.; and Anal. Calcd for C16H20N2.HCl: C, 69.41% H, 7.65% N, 10.12% and Found: C, 69.25% H, 7.55% N, 9.89%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([N:23]=[N+:24]=[N-:25])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 5-chloro-2-thiophene-carboxylic acid (5.00 g, 30.7 mmol) in 130 mL of acetone is added Et3N (4.29 mL, 30.7 mmol). The mixture is cooled to 0° C. and ethyl chloroformate (3.23 mL, 33.8 mmol) is added. The mixture is stirred at 0° C. for 1 h and sodium azide (3.40 g, 52.3 mmol) is added. The mixture is stirred at 0° C. for 2 h, then poured into 300 mL of ice water and the aqueous layer is extracted with CH2Cl2 (2×). The combined organics are washed with water (2×) and brine, then dried, filtered and concentrated. The crude residue is purified via flash column chromatography eluting with 10% EtOAc/hexanes to provide the title compound (3.00 g, 16.0 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.67 (d, 1H), 6.99 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([N+:14]([O-])=O)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])[CH3:2].[Cl-].[NH4+]>O.CO.[Fe]>[NH2:14][C:7]1[CH:6]=[C:5]([O:17][CH3:18])[C:4]([O:3][CH2:1][CH3:2])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOc1cc(C(=O)OC)c(N)cc1OC
Reaction time: 12 h

Procedure:
A mixture of 17.0 g (66.7 mmol) of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate, 13.1 g (233 mmol) of powdered iron and 17.7 g (334 mmol) of ammonium chloride in 95 mL of water and 245 mL of methanol was refluxed for 4.5 h. An additional 13.1 g of iron was added followed by refluxing for 2.5 h. Then an additional 13.1 g of iron and 17.7 g of ammonium chloride was added and refluxing was continued for 12 h. The reaction was filtered through Celite and methanol was removed from the filtrate. The filtrate was extracted with chloroform and the extracts were treated with Darco, evaporated and dried in vacuo (50° C.). The yield was 11.0 g of methyl 2-amino-5-ethoxy-4-methoxybenzoate as tan crystals: mass spectrum (electrospray, m/e): M+H 225.9.
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:9])#[CH:2].[CH3:11][CH2:12][NH:13][C:14]([C@H:16]1[O:20][C@@H:19]([N:21]2[C:25]3[N:26]=[C:27](I)[N:28]=[C:29]([NH2:30])[C:24]=3[N:23]=[CH:22]2)[CH:18]([OH:32])[C@H:17]1[OH:33])=[O:15]>>[CH2:12]([NH:13][C:14]([CH:16]1[CH:17]([OH:33])[CH:18]([OH:32])[CH:19]([N:21]2[CH:22]=[N:23][C:24]3[C:25]2=[N:26][C:27]([C:2]#[C:1][C:3]2([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH3:9])=[N:28][C:29]=3[NH2:30])[O:20]1)=[O:15])[CH3:11]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(I)nc32)C(O)[C@H]1O
Reactant: C#CC1(O)CCCCC1C
Product: CCNC(=O)C1OC(n2cnc3c(N)nc(C#CC4(O)CCCCC4C)nc32)C(O)C1O
Yield: 65 %

Procedure:
The reaction of 1-Ethynyl-2-methyl-cyclohexanol (JR3169B) (100 mg, 0.72 mmol) with 2-iodo-NECA (25 mg, 0.06 mmol) under the general coupling conditions gave JR3177A (8.0 mg) and JR3177B (8.2 mg) (overall yield 65%) as white solids after purification by a silica plug and RP-HPLC. JR3177A: 1H NMR (CD3OD-d4) δ 8.47 (s, 1 H), 6.05 (d, J=6.9 Hz, 1 H), 4.77 (dd, J=6.9 Hz, J=4.9 Hz, 1 H), 4.45 (d, J=1.9 Hz, 1 H), 4.34 (dd, J=4.6 Hz, J=2.1 Hz, 1 H), 3.41 (m, 2 H), 2.13 (d, J=12.7 Hz, 2 H), 1.65 (m, 5 H), 1.32 (m, 2 H), 1.14 (t, J=7.0 Hz, 3 H), 1.13 (d, J=6.6 Hz, 3 H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.3 (MH+, 100), 427.4 (80), 254.4 (14). 1H NMR (CD3OD-d4) δ 8.49 (s, 1 H), 6.05 (d, J=6.9 Hz, 1 H), 4.78 (dd, J=6.4 Hz, J=4.9 Hz, 1 H), 4.45 (d, J=1.9 Hz, 1 H), 4.34 (dd, J=4.6 Hz, J=1.6 Hz, 1 H), 3.42 (m, 2 H), 2.12 (d, J=12.3 Hz, 2 H), 1.65 (m, 4 H), 1.35 (m, 4 H), 1.14 (t, J=7.3 Hz, 3 H), 1.12 (d, J=6.6 Hz, 3 H). 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 445.7 (MH+, 100), 427.3 (35), 254.4 (3.5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:17][CH:18]=C)[CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8].[O:21]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([CH2:17][CH:18]=[O:21])[CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: C=CCC(C(=O)OC)C(CC(=O)O)c1cccc(F)c1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CC=O)C(CC(=O)O)c1cccc(F)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2-allyl-3-(3-fluoro-phenyl)-pentanedioic acid 1-methyl ester (2-5) (1.01 g, 3.28 mmol) and Sudan Red B (0.01 g) in 100 mL CH2Cl2 was treated with ozone at -78° C. for 20 min. Then excess ozone was purged with argon, followed with the addition of PPh3 (2.00 g, 7.63 mmol). The mixture was stirred for 30 min and concentrated under diminished pressure. The residue was purified by flash silica chromatography (EtOAc/Hexane, 1:3) to provide the desired product as two separated pairs of enantiomers (2-6A and 2-6B).