Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[IH:12]>O>[I:12][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: I
Solvent: O
Product: Nc1nc(I)c2nc[nH]c2n1
Reaction time: 1.5 h

Procedure:
6-Chloro-9H-purin-2-amine (5.0 g., 29.5 mmole) was added to 47% hydrogen iodide (61 ml., 12.2 ml./g.) chilled in an ice bath. After 1.5 hours, water (61 ml.) was added and the mixture stirred in an ice-bath for 30 minutes. The yellow solid was filtered out and the filter cake was washed with water. The wet solid was transferred to a beaker and the residue in the funnel was washed into the beaker with water (30 ml.). 6M Sodium hydroxide (7 ml.) was added with stirring until all the solid had dissolved (pH 14). The solution was added to boiling water (30 ml.) containing acetic acid (3 ml.). The mixture was boiled briefly and allowed to stand at room temperature for one hour. The product was filtered off, washed with water, and dried under vacuum overnight to give 6.88 g. of the desired product; m.p. about 240° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[ClH:11].[CH3:12]O>>[ClH:11].[CH3:12][O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCCCCC(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCN
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 7-amino-heptanoic acid (3.0 g, 21.0 mmol), in 25 mL MeOH and 2.4 mL concentrated HCl was heated at reflux for 4 hours and was stirred at room temperature for 60 h. The mixture was concentrated in vacuo to afford the title compound (3.3 g). 1H NMR (400 MHz, CD3OD) δ 3.62 (s, 3H), 2.89 (m, 2H), 2.31 (t, 2H), 1.62 (m, 4H), 1.37 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1.F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=c1n(CCCF)nnn1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1cc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)cc1F

Procedure:
1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one is etherified with 4-fluoronitrobenzene in the presence of potassium carbonate in N,N-dimethylformamide to form 1-[4-chloro-2-fluoro-5-(4-nitrophenoxy)phenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound A). Compound A is then reduced with iron powder in acetic acid and water to produce 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one (Compound B). Acetone is added to a stirring mixture of Compound B in hydrochloric acid. The mixture is cooled to about 5° C., and a solution of an equimolar amount of sodium nitrite in water and a molar excess of methyl acrylate are added in succession. The resultant mixture is stirred for 15-20 minutes, after which copper (I) chloride is slowly added. The mixture is stirred at room temperature for approximately 30 minutes and then poured into ice water. The resulting mixture is then treated with an organic solvent (e.g., ethyl acetate) to extract the product, methyl 2-chloro-3-[4-[2-chloro-4-fluoro-5-[4-(3-fluoropropyl)-1,4-dihydro-5H-5-oxo-tetrazol-1-yl]phenoxy]phenyl]propionate, which may then be purified, as by column chromatography on silica gel.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([CH3:32])[C:23]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:54]>C(O)C>[Na+:54].[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([CH3:32])[C:23]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: COc1ccc(C(C)C)cc1-c1c(C)cc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1c(C)cc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (20 mg) is dissolved in ethanol (2 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (0.5 ml) and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (21 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 1N-aqueous sodium hydroxide solution (28 μl) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-6-methyl-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (19 mg). MS (m/z): 742 [M−Na]−
Reaction SMILES: [Zn](CC)[CH2:2]C.C(I)I.[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]=[C:18]([CH2:22][OH:23])[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>C(Cl)Cl>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]2[C:18]([CH2:22][OH:23])([CH2:2]2)[CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCC1=CCCN(Cc2ccccc2)C1
Reactant: CC[Zn]CC
Agent: Cl
Solvent: ICI
Solvent: ClCCl
Product: OCC12CC1CCN(Cc1ccccc1)C2
Reaction time: 0.25 h

Procedure:
To a solution of ZnEt2 (17.3 ml, 1.0 M) in CH2Cl2 (20 ml) at 0° C. was added CH2I2 (1.4 ml) (CAUTION: exothermic!). After stirring for 15 min, a solution of 172 (352 mg, 1.73 mmol) in CH2Cl2 (2 ml) was added. The mixture was stirred from 0° C. to room temperature overnight. 5% HCl was added to bring the mixture to a homogeneous solution. (white solid dissolved). The two layers were separated. Aqueous layer was neutralized with 2N KOH to pH=10–12, extracted with CH2Cl2 (twice). The combined organic solution was dried (K2CO3/Na2SO4), filtered and concentrated. The LRMS of the crude mixture showed that the ratio of 173 to 172 was about 1:1. The product was not isolated from the starting material due to their similar polarities. LRMS (calculated for C14H19NO) 217. found 217.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:20](=[O:21])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([N:17]=[N+]=[N-])[C:11]=4[CH:10]=[CH:9][N:8]=3>N1CCCCC1.CO>[CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]4[C:13]([C:20](=[O:21])[C:4]2=[CH:3][CH:2]=1)=[N:14][CH:15]=[C:16]([NH2:17])[C:11]=4[CH:10]=[CH:9][N:8]=3
Reactant: [N-]=[N+]=Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Solvent: C1CCNCC1
Solvent: CO
Product: Nc1cnc2c3c(nccc13)-c1ccccc1C2=O
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Hydrogen sulfide was bubbled through a solution containing 4-azidosampangine (160 mg, 0.58 mmol) and piperidine (2 drops) in MeOH (20 mL) that was precooled to 10° C. After 30 min, the temperature of the reaction was allowed to rise to ambient temperature, and after an additional 30 min the reaction was stopped. The solvent was evaporated and the residual solids chromatographed over silica using CHCl3 /MeOH (9:1) as eluant to give 4-aminosampangine (136 mg, 95%). The chromatography of 4-aminosampangine (23) is easily monitored through its fluorescent characteristics. An analytical sample was obtained by crystallization from DMSO: mp>325° C.; UV (MeOH) 207 (log ε 4.34), 252 (log ε 4.16), 269 (log ε 4.15), 348 (log ε 3.56), 461 (log ε 4.11); IR (KBr) 3300 (br) 1725, 1625, 1585, 1560, 1505, 1460, 1385, 1335, 1300, 1125, 1070, 725 cm-1 ; 1H NMR (DMSO-d6) δ7.72 (ddd, 1 H, J=7.5, 7.5, 1.3 Hz), 7.83 (ddd, 1 H, J=7.5, 7.5, 1.3 Hz), 7.95 (br s, 2 H), 8.21 (d, 1 H, J=5.9 Hz), 8.26 (dd, 1 H, J=7.5, 1.3 Hz), 8.38 (s, 1 H), 8.75 (dd, 1 H, J=7.5, 1.3 Hz), 8.81 (d, 1 H, J=5.9 Hz); 13C NMR (DMSO-d6) 115.7 (1), 119.8 (0), 124.1 (0), 124.7 (1), 127.0 (1), 130.9 (1), 132.0 (1), 132.8 (0), 132.9 (0), 133.1 (1), 134.7 (0), 144.3 (1), 145.1 (0), 148.5 (0), 178.4 (0) ppm; Anal. calcd for C15H9N3O.H2O: C 67.92, H 4.18, N 15.83; found C 68.30, H 3.80, N 15.75.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]>>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[C@H:15]([CH3:16])[C@H:22]([C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Br:18])[CH:20]=1)[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](O)c1cccc(Br)c1
Yield: 76 %

Procedure:
The title compound (2.73 g, 76%) was prepared from 4-(S)-benzyl-3-propionyl-oxazolidin-2-one and 3-bromobenzaldehyde as in Example 55, Part B. 1H NMR (400 MHz, CDCl3): 7.59-7.56 (m, 1H), 7.42-7.38 (m, 1H), 7.37-7.28 (m, 4H), 7.25-7.18 (m, 3H), 5.11 (app t, J=2.8, 1H), 4.73-4.64 (m, 1H), 4.22-4.16 (m, 2H), 4.02 (dq, J=7.0, 3.3, 1H), 3.27 (d, J=2.6, 1H), 3.25 (dd, J=13.4, 3.4, 1H), 2.80 (dd, J=13.4, 9.4, 1H), 1.18 (d, J=7.0, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:15]/[CH:16]=[C:17](\[CH3:23])/[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH3:2].[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([OH:14])[C:4]=1[CH2:15]/[CH:16]=[C:17](\[CH3:23])/[CH2:18][CH2:19][C:20]([O:22][CH3:24])=[O:21])[CH3:2]
Reactant: CCc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CCc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (E)-6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in methanol (200 ml) was treated with p-toluenesulfonic acid (0.8 g) and stirred at 25° C. for 16 hours. The reaction mixture was cooled to 0° C. Methyl (E)-6-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, m.p. 116.5°-117.6, was collected by filtration.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:59]=[CH:58][C:12]2[N:13]([CH2:43][C:44]([N:46]([CH:55]([CH3:57])[CH3:56])[C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)=[O:45])[C:14](=[O:42])[CH:15]([CH2:25][C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28](C(OC(C)(C)C)=O)[N:27]=3)[C:16](=[O:24])[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1>>[F:8][C:9]1[CH:59]=[CH:58][C:12]2[N:13]([CH2:43][C:44]([N:46]([CH:55]([CH3:57])[CH3:56])[C:47]3[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=3)=[O:45])[C:14](=[O:42])[CH:15]([CH2:25][C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][N:27]=3)[C:16](=[O:24])[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:11]=2[CH:10]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
To a solution of 5 mL of trifluoroacetic acid under nitrogen is add 364 mg of 2-[7-fluoro-3-(1-tertbutoxycarbonyl-indazol-3-ylmethyl)-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 66. After stirring at ambient temperature for 20 min, the reaction mixture is evaporated in vacuo and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer is back-extracted with dichloromethane. The organic layers were combined, washed with aqueous sodium hydroxide (1N), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue is triturated with hexane, the hexane is removed in vacuo, and the residual solid is dried under high vacuum to provide 286 mg of the title compound as a white solid: 1H NMR (300 MHz, CDCl3) δ8.67 (s, br, 1H), 8.56 (dd, 1H, J=1.5, 5.2), 8.10 (d, 1H, J=8.1), 7.82 (d, 1H, J=8.1), 7.52 (dd, 1H, J=5.3, 8.3), 7.35 (m, 3H), 7.14 (m, 3H), 7.03 (m, 1H), 6.96 (m, 3H), 6.61 (dd, 1H, J=2.7, 8.9), 4.92 (m, 1H), 4.51 (d, 1H, J=15.8), 4.29 (dd, 1H, J=5.8, 7.7), 4.05 (d, 1H, J=16.0), 3.84 (s, 3H), 3.78 (dd, 1H, J=7.8, 16.4), 3.61 (dd, 1H, J=5.9, 16.2), 1.03 (d, 6H, J=6.8); low resolution MS (FAB)m/e 607 (MH+).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>>[ClH:16].[CH3:18][N:19]([CH3:20])[CH:21]([C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH3:22]
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CN(C)CCCl
Agent: Cl
Product: CC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N(C)C
Yield: 104.2 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-chloroindazole (4.57 g) and dimethylaminoethyl chloride hydrochloride (4.32 g) were treated to obtain 3.5 g of 1-dimethylaminoethyl-3-phenyl-5-chloroindazole hydrochloride (m.p. 200°-201° C).
Reaction SMILES: O[CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[NH:9]=[N+:10]=[N-:11].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:9]([CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)=[N+:10]=[N-:11]
Reactant: O=C1CC[C@H](CO)N1
Reactant: [N-]=[N+]=N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To (R)-5-(hydroxymethyl)pyrrolidin-2-one (660 mg, 5.73 mmol), hydrogen azide (10.8 mL, 8.60 mmol, 0.8 M in toluene), and PPh3 (2.25 g, 8.60 mmol) in THF was added DIAD dropwise. The mixture was stirred at rt for 1 h. LCMS indicated the completion of the reaction. The mixture was partially concentrated, filtered, and purified by RP-HPLC to give (R)-5-(azidomethyl)pyrrolidin-2-one (730 mg, 87%, 90% pure). LRMS (M+H+) m/z 141.1.
Reaction SMILES: [Br:1]Br.[CH:3]1([S:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:5][CH2:4]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[Br:1][C:10]1[CH:11]=[CH:12][C:7]([S:6][CH:3]2[CH2:5][CH2:4]2)=[C:8]([CH3:13])[CH:9]=1
Reactant: Cc1ccccc1SC1CC1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1SC1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
Bromine (0.42 mL) was added to a solution of 1-(cyclopropylsulfanyl)-2-methylbenzene (1.35 g) in acetic acid (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction solution was ice-cooled and a saturated sodium thiosulfate solution and brine were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) and the solvent was evaporated under reduced pressure. The precipitated solid was filtered and washed with hexane, after which the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a pale yellow oil (1.59 g, 80%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([O:28]CC5C=CC(OC)=CC=5)[CH:23]=4)=[N:17][CH:18]=[CH:19][CH:20]=3)[N:12]=[C:11]([CH3:38])[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[NH2:8][C:9]1[N:10]=[C:11]([CH3:38])[N:12]=[C:13]([C:15]2[C:16]([NH:21][C:22]3[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[N:14]=1
Reactant: COc1ccc(COc2cc(Nc3ncccc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)ccn2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2cc[nH]c(=O)c2)n1
Yield: 18.5 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-(2-(4-methoxybenzyloxy)pyridin-4-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.120 g, 0.183 mmol) in trifluoroacetic acid (Aldrich) (1.631 mL, 21.96 mmol) and trifluoromethane sulfonic acid (TCI) (0.810 mL, 9.15 mmol) was heated at 80° C. in a sealed tube for 1 h. The reaction mixture was neutralized with sat. NaHCO3.The precipitate was collected by filtration. The precipitate was purified by prep HPLC to give the product as a white solid (0.010 g). m/z (ESI, +ve ion) 296.1 (M+H)+. 1H NMR (300 MHz, d6-DMSO) δ 12.14 (s, 1H); 10.94 (br. s., 1H); 8.81 (d, J=6.87Hz, 1H); 8.46 (d, J=4.09 Hz, 1H); 7.66-8.04 (m, 2H); 7.24 (d, J=7.31 Hz, 1H); 7.19 (s, 1H); 7.08 (dd, J=7.97, 4.75 Hz, 1H); 6.53 (d, J=5.70 Hz, 1H); 2.44 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH2:21])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[CH2:19][CH2:18][CH:17]([NH:21][C:31](=[O:34])[CH2:32][CH3:33])[C:16]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
A solution of (rac)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6,7-dihydro-5H-[2]pyrindin-7-ylamine (example 89) (40 mg, 0.14 mmol) and N,N-diisopropylethylamine (0.071 mL, 0.41 mmol) in DMF (0.5 mL) was treated with propionyl chloride (0.018 mL, 0.20 mmol) and the reaction mixture stirred at room temperature overnight. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.0 mg (7%) of the title compound as a light brown oil. MS: 353.5 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:8]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: BrCCCCCBr
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCCCC1

Procedure:
The title compound was synthesized from 2-(4-(trifluoromethyl)phenyl)-acetonitrile (4.11 g, 22.2 mmol) and 1,5-dibromopentane (3.324 ml, 24.4 mmol) according to General Procedure J and was obtained as a clear oil (4.98 g, 89%). 1H NMR (CDCl3) δ 1.23-1.39 (m, 1H), 1.76-1.92 (m, 7H), 2.17 (d, J=11.2 Hz, 2H), 7.63 (s, 4H). 13C NMR (CDCl13) δ 23.7, 25.0, 37.4, 44.7, 122.2, 126.0, 126.7, 130.2, 145.6,GC-MS m/z 253.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[CH2:12]=[C:13]([CH2:16][CH2:17][C:18]#[N:19])[C:14]#[N:15].C(O)C>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]#[N:19])[C:14]#[N:15]
Reactant: Sc1ccc2ccccc2c1
Reactant: C=C(C#N)CCC#N
Solvent: CO
Solvent: CCO
Product: N#CCCC(C#N)CSc1ccc2ccccc2c1

Procedure:
A mixture of 2-naphthalenethiol (10.0 g), 2-methyleneglutaronitrile (6.8 ml), ethanol (150 ml), and triton B (40% methanol solution, 10 drops) was refluxed for 2 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with water, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 15.6 g of 2-(2-naphthylthiomethyl)glutaronitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li+].CC([N-]C(C)C)C.[C:18](=[O:20])=[O:19]>C1COCC1>[F:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[C:6]([I:8])[C:7]=1[C:18]([OH:20])=[O:19]
Reactant: Cc1ccc(I)cc1F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(I)c(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A −78° C. solution of 2-fluoro-4-iodo-1-methylbenzene (25 g, 105.9 mmol) in THF (200 mL) was treated dropwise with LDA (2M solution in THF, 58.5 mL, 116 mmol), stirred at −78° C. for 1 hour, treated with excess powdered dry ice, stirred at −78° C. for 30 minutes, and warmed to room temperature gradually over about 18 hours. The mixture was concentrated and the residue was partitioned between 4N NaOH and diethyl ether. The aqueous phase was adjusted to pH 2 with 2N HCl and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 19.4 g (66% yield) of the desired product. MS (ESI(+)) m/e 279 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.S(OC)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O1CCOCC1.CC(C)=O.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:19]([OH:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:22])=[C:13]([Cl:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)c(Cl)c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1Cl
Yield: 86 %

Procedure:
Protected amino acid I was prepared from D-tyrosine in five steps. First, D-tyrosine was chlorinated with sulfuryl chloride in glacial acetic acid (R. Zeynek, Hoppe-Seyler's Z. f. Physiol. Chemie 1926, 144, 247-254). Next N-(tert-butoxycarbonyl)-3-(3-chloro-4-hydroxyphenyl)-D-a lanine was obtained in 94% yield by treating a suspension of the amino acid in 50% aqueous dioxane with di-tert-butyldicarbonate in the presence of triethylamine. The resulting product was dimethylated with dimethyl sulfate in the presence of potassium carbonate in refluxing acetone in 84% yield. The methyl ester was then saponified with sodium hydroxide in aqueous dioxane to yield N-(tert-butoxycarbonyl)-3-(3-chloro-4-methoxyphenyl)-D-a lanine in 86% yield. Exposure of the BOC-protected amino acid to trichloroethanol, pyridine and DCC in dichloromethane led to trichloroethyl ester I in 65% yield. Treatment of this material with trifluoroacetic acid led to a quantitative yield of the trifluoroacetate salt of I.