Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])=[C:4](OC)[CH3:5])#[N:2].C(=O)(O)O.[NH2:25][C:26]([NH2:28])=[NH:27].O>CN(C)C(=O)C>[NH2:27][C:26]1[N:28]=[C:1]([NH2:2])[C:3]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:20])[F:19])=[C:4]([CH3:5])[N:25]=1
Reactant: COC(C)=C(C#N)CCCc1ccccc1C(F)(F)F
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(N)nc(N)c1CCCc1ccccc1C(F)(F)F
Yield: 40.6 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 7.6 grams (0.027 mole) of 3-cyano-2-methoxy-6-(2-trifluoromethylphenyl)-2-hexene and 12.2 grams (0.068 mole) of guanidine carbonate in 35 mL of N,N-dimethylacetamide was heated at about 150° C. for 40 hours. After this time, the reaction mixture was poured into 300 mL of water. The resultant solid was collected by filtration, and was then slurried in 100 mL of diethyl ether. The solid was again collected by filtration and was subjected to column chromatography on silica gel. Elution was accomplished using 10% methanol in methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 2,4-diamino-5-[3-(2-trifluoromethylphenyl)propyl]-6-methyl-pyrimidine, mp 151°-158° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1OC)[CH:9]=2)=[O:4].[NH2:27][C@H:28]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31].CCN(CC)CC>CO>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][C@H:28]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:29]([OH:34])[C:30]([O:32][CH3:33])=[O:31])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 150 °C

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester (20 mg, 0.06 mmol), (2R,3R)-methyl 3-amino-2-hydroxy-4-phenylbutanoate (43 mg, 0.13 mmol) and Et3N (0.04 mL, 0.27 mmol) in MeOH (2 mL) was heated at 150° C. in a microwave for 3 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-10% EtOAc/CH2Cl2) to give the title compound in 7 mg. MS: (−) m/z 496.34 (M-1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([Br:12])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2c(N)cccc2o1
Solvent: CN(C)C=O
Product: Cc1nc2c(N)ccc(Br)c2o1
Temperature: -5 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
Compound 474B (3.90 g, 26.3 mmol) was dissolved in DMF (45 mL) and cooled to −5° C. and N-bromosuccinimide (4.68 g, 26.3 mmol) was added in small portions and the reaction stirred for 5 h. The mixture was poured into 150 mL of ice water to give a cream colored solid which was filtered, washed with water, dissolved in CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material by flash chromatography on silica gel eluting with 20% ether/CH2Cl2 gave compound 474C (3.36 g, 56%) as a beige solid. HPLC: 95.4% at 2.583 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): f/z 228.03 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cu][C:15]#[N:16].C(N)CN>CN1CCCC1=O>[C:15]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH:8]=[CH:9]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: N#C[Cu]
Reactant: CC1(C)C=Cc2cc(Br)ccc2C1
Solvent: CN1CCCC1=O
Solvent: NCCN
Product: CC1(C)C=Cc2cc(C#N)ccc2C1
Yield: 96 %

Procedure:
A solution of 7-bromo-3,3-dimethyl-3,4-dihydronaphthalene (6.2 g) and copper (1) cyanide (3.5 g) in N-methylpyrrolidone (60 ml) was heated under reflux for 2 hours. After cooling, the mixture was poured into 10% aqueous ethylenediamine (200 ml) and extracted into ethyl acetate. The combined extracts were washed with water, and dried over magnesium sulphate. Solvent and drying agent were removed and the residue chromatographed on silica gel using ether-pentane (1:10) as eluant gave the dihydronaphthalene as a white crystalline solid (4.6 g), having mp 50°-52° C.;
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:4]=1[C:5]([OH:7])=[O:6].[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[C:4]=1[C:5]([O:7][CH3:24])=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: O=C(O)c1c(C(F)(F)F)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6 g of 2,6-bis-trifluoromethyl-benzoic acid, 60 ml of tetrahydrofuran and 11.58 ml of a 2N sodium hydroxide solution was stirred for 30 minutes at 20° C. and after the reaction medium was cooled to 0° C., 4.26 ml of dimethyl sulfate were added. The mixture was stirred for 1 hour at 20° C. and another 2.1 ml of dimethyl sulfate were added. The reaction mixture was stirred for 24 hours at 20° C. and was then poured into an aqueous solution of sodium bicarbonate, extracted with isopropyl ether, then with ethyl acetate, dried, filtered, rinsed and brought to dryness. After chromatographing on silica (eluant hexane-ethyl acetate (9-1)), 5.59 g of the desired product were obtained.
Reaction SMILES: [H-].[K+].[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][OH:21])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22]I>O1CCCC1>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([CH2:20][O:21][CH3:22])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCC1Cc2ccccc2N(Cc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1Cc2ccccc2N(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
2.3 g of a potassium hydride suspension (20% in oil) are added to a solution of 2.6 g of 1-benzyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline in 30 ml of tetrahydrofuran at 0° C., while stirring, and 1.9 ml of methyliodide are then added. After 1 h, the reaction mixture is concentrated and the residue is purified over 160 g of silica gel with a 20:1 mixture of hexane and ethyl acetate. 1-Benzyl-3(R,S)-methoxymethyl-1,2,3,4-tetrahydroquinoline is obtained as a yellow solid: Rf (20:1 mixture of hexane and ethyl acetate)=0.32. A solution of 2.9 g of the product thus obtained in 30 ml of tetrahydrofuran is hydrogenated in the presence of 0.6 g of palladium-on-charcoal under the customary conditions. Purification of the crude product over 80 g of silica gel with methylene chloride as the eluting agent gives 3(R,S)-methoxymethyl-1,2,3,4-tetrahydroquinoline: Rf (methylene chloride)=0.32; Rf (A)=0.56.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[C:15]1([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Yield: 80.6 %

Procedure:
Methyl 2-bromo-1H-indole-3-carboxylate (200 mg, 0.79 mmol), phenylboronic acid (122 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) and cesiumcarbonate (652 mg, 2 mmol) in dioxane/water (20 mL/5 mL) were stirred at room temperature 15 hours. Filterated the solid and the solvent was concentrated in vacuum. The resulted residue was purified by silica gel column (ethyl acetate:petroleum ether=1:2) to obtain methyl 2-phenyl-1H-indole-3-carboxylate as a pale yellow solid (160 mg, 80%) LRMS (M+H+) m/z: calcd 251.1 found 251.
Reaction SMILES: [CH2:1]([NH:15][CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH:16]1([N:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The preparation is analogous to Example 12 from N-tetradecyl-glucopyranosylamine and stearoyl chloride.
Reaction SMILES: [N:1]([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1[N:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])=[N+:2]=[N-:3].[I:20]Cl.CCOCC>CO>[I:20][C:18]1[C:16](=[O:17])[NH:15][C:13](=[O:14])[N:12]([CH:19]=1)[C@@H:5]1[O:6][C@H:7]([CH2:10][OH:11])[C@@H:8]([OH:9])[C@H:4]1[N:1]=[N+:2]=[N-:3]
Reactant: ClI
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CO
Solvent: CCOCC
Product: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
To a solution of 2'-azido,2'-deoxyuridine (2.5 g, 9.3 mmoles) in methanol (20 ml) is added ICl (3.3 g, 20.5 mmoles, 2.2 eq.). The mixture is heated at 50° C. for 30 min. After cooling to room temperature, an equal volume of ether is added and the white precipitate is filtered off. The precipitate is stirred in methanolic ammonia (20 ml) at room temperature for 15 min, and then evaporated to dryness to yield 2.81 g (76%) of 5-iodo,2'-azido,2'-deoxyuridine. 1H NMR (300 MHz, methanol -d4) δ 8.58 (s, 1H, H6), 5.88 (d, 1H, H1', JH1'H2' =3.5 Hz), 4.46 (t, 1H, H3', J=5.8 Hz), 4.11 (dd, 1H, H2', JH1',H2' =3.9 Hz, J H2',H3' =5.3 Hz), 4.01 (m, 1H, H4'), 3.91 (dd, 1H, H5'AJgem =12.3 Hz, JH5',H4' =2.4 Hz) 3.76 (dd, 1H, H5'B, Jgem =12.3 Hz, JH5',H4' =2.4 Hz). 13C NMR (75 MHz, methanol-d4) δ 163.03, 152.17, 146.50, 88.88, 86.18, 71.21, 67/67, 61.00, 48.15. FAB mass spectrum, (M+H) m/z 396.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH3:16])[C:4](=[O:17])[C:3]1=[O:18].[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:20]1=2.C(N(CC)CC)C>ClCCl>[O:19]1[CH2:24][CH2:23][O:22][C:21]2[CH:25]=[C:26]([NH:29][S:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]([CH3:1])[C:3](=[O:18])[C:4](=[O:17])[N:5]4[CH3:16])(=[O:14])=[O:13])[CH:27]=[CH:28][C:20]1=2
Reactant: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c(=O)n(C)c2cc(S(=O)(=O)Nc3ccc4c(c3)OCCO4)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonyl chloride (example 6-3a, 450 mg, 1.6 mmol) was added to a stirred solution of the 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (215 mg, 1.4 mmol) and triethylamine (170 mg, 1.7 mmol) in dichloromethane (10 mL). The reaction was stirred at ambient temperature overnight then concentrated. The crude product was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to provide N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. MS (M+H, 404.10); 1H NMR (400MHz, DMSO-d6): δ, ppm: 3.47 (s, 3H), 3.49 (s, 3H), 4.12 (m, 4H), 6.55 (m, 1H), 6.61 (d, J=2.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 7.59 (d, J=2 Hz, 1H), 10.00 (s, 1H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11].O.C(O)(=O)C.[CH2:18]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:19]([CH3:21])[CH3:20]>>[CH3:20][CH:19]([CH3:21])[CH2:18][N:22]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CCCCC=O
Reactant: CC(C)CNCC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCN(CC(C)C)CC(C)C
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a suspension of magnesium sulfate (10.1 g) in diisobutylamine (72.0 g) was added dropwise valeraldehyde (24.6 g) at 0-5° C. under a nitrogen atmosphere, and it was stirred at 10-15° C. for 1 hour. After ice-cooling, water (60 ml) was added and it was stirred to dissolve the magnesium sulfate. After the removal of the aqueous layer, to the organic layer obtained was added a 9% (w/v) aqueous acetic acid solution (200 ml) at 0-5° C. and then stirred for 5 minutes. The aqueous layer was, then, removed again, a 0.5% (w/v) aqueous sodium hydroxide solution (60 ml) was added to the organic layer at 0-5° C., and stirred for 5 minutes. After stirring, the aqueous layer was removed to afford the title compound (51.3 g, yield: 80%, purity: 93.8%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=[O:13])[N:11]=1)=[O:5].S([CH2:39][N+:40]#[C-:41])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:10]([C:12]2[O:13][CH:41]=[N:40][CH:39]=2)[N:11]=1)=[O:5]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1nc(-c2cnco2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Temperature: 65 °C
Yield: 72.4 %

Procedure:
Into a solution of Compound 67 (62 mg, 0.15 mmol) in 5 mL of dry methanol was added tosylmethyl isocyanide (35 mg, 0.18 mmol), followed by dry potassium carbonate (25 mg, 0.18 mmol). The reaction mixture was heated to 65° C. for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed each with water and brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluted with 10-50% ethyl acetate in hexanes) to give Compound 76 (49 mg, 72%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]3)[CH:6]=[CH:7][CH:8]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)([OH:31])[CH2:27][CH2:26]1>>[OH:31][C:28]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C@H:37]([OH:40])[C@@H:36]([CH3:41])[CH2:35]2)[CH2:29][CH2:30][CH:25]([NH:24][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:26][CH2:27]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cccc(CCOc2cccc3[nH]c(C(=O)O)cc23)c1
Product: COc1cccc(CCOc2cccc3[nH]c(C(=O)NC4CCC(O)(CCN5CC[C@H](O)[C@@H](C)C5)CC4)cc23)c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(3-methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid 16k and amine 14.
Reaction SMILES: [Mg].[Cl-].[CH3:3][CH2:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12](Br)[C:13]#[CH:14].S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1>[OH:11][C:6]([CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:5][C:4]#[CH:3]
Reactant: CCCCC(=O)CCC
Reactant: C#CCBr
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: C#CCC(O)(CCC)CCCC

Procedure:
14 Grams of powdered (50 mesh) magnesium metal is suspended in 80 ml of ether and activated by addition of 200 mg of mercurie chloride. A solution of 38.4 g of 4-octanone and 36.6 g of propargyl bromide in 120 ml of ether and 50 ml of benzene is added dropwise at a rate which produced a gentle reflux. After the addition is complete, the reaction mixture is stirred for several hours and is then poured into 500 ml of cold 5% sulfuric acid. The organic layer is separated, washed with water twice, dried over sodium sulfate and stripped of solvent. The residue is distilled under vacuum to give the title product.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13]O.S(=O)(=O)(O)O.O>C(OCC)C>[CH3:13][O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: COC(=O)C=Cc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A one liter round bottom flask was charged with 50 grams (0.30 moles) of 4-fluorocinnamic acid, 500 milliliters of methanol, and 5.0 grams of concentrated sulfuric acid. This mixture was brought to reflux and kept there for 18 hours. After cooling, one half of the methanol was stripped under vacuum, and the remaining solution was poured into 600 milliliters of water. The precipitated solid was taken into 500 milliliters of diethyl ether and the aqueous phase was discarded. The ether solution was washed three times with 10% aqueous sodium hydroxide and once with water. After drying over magnesium sulfate, the mixture was filtered and stripped under vacuum to give methyl-4-fluorocinnamate as a white crystalline powder. Yield was 40 grams.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12].[C:16]([O:20][C:21]([N:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH2:14]([S:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:24]1[N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH:27]=[CH:26][CH:25]=1)(=[O:13])=[O:12])[CH3:15]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
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: COCCOC
Product: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1cccn1C(=O)OC(C)(C)C
Temperature: 97 °C
Yield: 91.6 %

Procedure:
To 100B (3.48 g, 11.8 mmol), 3A (3.0 g, 14.2 mmol) and sodium carbonate (23.7 mL, 2M, 47.4 mmol) in 1,2 dimethoxyethane (100 mL, flushed and degassed (3×) with nitrogen) was added Pd(PPh3)4 (2.74 g, 2.37 mmol). The reaction was heated to 97° C. for 3 h. The catalyst was filtered over celite and washed with ethyl acetate. The organic layer was washed with water, brine and then dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 4.11 g of product 10° C. (91% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.09 (t, J=7.46 Hz, 3H) 1.25 (s, 9H) 2.87-3.04 (m, 2H) 6.24-6.44 (m, 2H) 7.46 (dd, J=3.30, 1.83 Hz, 1H) 8.24 (d, J=2.20 Hz, 1H) 8.31 (d, J=8.56 Hz, 1H) 8.45 (dd, J=8.80, 2.45 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([OH:16])=[CH:11][C:10]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=1[CH2:58][OH:59]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][C:52]=2[CH2:58][OH:59])=[CH:11][C:10]1=[O:17]
Reactant: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Reactant: OCc1ccc(F)cc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2CO)cc(=O)n1-c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1-(2,6-Difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (step 1) (3.0 g, 12.65 mmol) was dissolved in N,N-dimethylformamide and cooled to 0° C. Triphenylphosphine (3.98 g, 15.18 mmol) and diethyl azodicarboxylate (2.39 ml, 15.18 mmol) were added and stirred for 10 minutes. 1,2-Bis(hydroxymethyl)-4-fluorobenzene (2.57 g, 16.44 mmol) was added and stirred at 0° C. for 1 hour, then allowed to warm to room temperature and stirred overnight. LC-MS showed only 1 product, not a mixture of regioisomers, as expected. The reaction was added to water and extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated. A Biotage silica column was done using 60% ethyl acetate/hexanes as an eluent. Desired product, with a substantial impurity was obtained. Another Biotage silica column was ran using 30% ethyl acetate/hexanes to obtain pure product. The resulting oil was triturated with diethyl ether to obtain a white solid (720 mg, 15%). 1H NMR (300 MHz, CDCl3) δ 7.51-7.39 (m, 2H), 7.26 (dd, J=9.62, 2.51 Hz, 1H), 7.13-7.01 (m, 3H), 6.03 (d, J=2.42 Hz, 1H), 5.96 (d, J=2.41 Hz, 1H), 5.06 (s, 2H), 4.73 (s, 2H), 2.81 (br s, 1H), 2.02 (s, 3H); LC/MS, tr=2.37 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50° C.), ES-MS m/z 376 (M+H). ES-HR/MS m/z 376.1181 (M+H calcd for C20H16F3NO3 requires 376.1155). Identity of the positional isomer was determined from hmbc, 2-D NMR experiments using H to C 2- and 3-bond coupling.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[CH:25][C:23](N)=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4F)c3c2s1
Yield: 56 %

Procedure:
Prepared from VII and 4-chloro-2-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 56%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2231, 1638, 1614, 1583, 1476, 1413, 1380, 1356, 1309, 1273, 1200, 1170, 1120, 982, 901, 838, 820; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=9.0 Hz), 8.24 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.34 (t, 1H, J=8.4 Hz), 7.26 (d, 1H, J=9.0 Hz); HRMS calcd for C16H8N5SClF (M+H+): 356.0173, found 356.0160.