Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]([C:26]([F:29])([F:28])[F:27])=[CH:7][C@@H:8]1[C@H:10]([C:11]([O:13][CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17](N)[C:16]=2[CH3:23])=[O:12])[C:9]1([CH3:25])[CH3:24].S(=O)(=O)(O)O.[I-:35].[K+]>O.[Cu]>[Cl:5][C:6]([C:26]([F:29])([F:28])[F:27])=[CH:7][C@@H:8]1[C@H:10]([C:11]([O:13][CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([I:35])[C:16]=2[CH3:23])=[O:12])[C:9]1([CH3:25])[CH3:24]
Reactant: Cc1ccc(N)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Reactant: [I-]
Agent: [Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(I)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A solution of sodium nitrite (12.7 g) in water (15 ml) was added dropwise to a stirred mixture of (3-amino-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (9.5 g, 0.025 mole) and concentrated sulfuric acid (20.9 g) in water (120 ml), while maintaining the temperature at 0°. The mixture was stirred at 0° for an additional 0.5 hour, and concentrated sulfuric acid (5 ml) was added. A solution of potassium iodide (34.8 g) in water (25 ml) was added dropwise, followed by copper powder (0.2 g). The reaction mixture was slowly heated to 70°. After heating at 70° for one hour the reaction mixture was allowed to cool and was stirred for 16 hours. The reaction mixture was then extracted with three 300 ml portions of methylene chloride. The combined extracts were washed twice with 500 ml of saturated aqueous sodium bisulfite solution and once with 500 ml of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent evaporated to give (3-iodo-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (9.89 g).
Reaction SMILES: C(OC(N(C)[C@@H](C)C(N[C@@H](C(C)(C)C)C(N1[C@H](C(N[C@@H](CC2C=CC=CC=2)C(O)=O)=O)CC2C(=CC([C@H]3C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](N(C(OC(C)(C)C)=O)C)C)C(C)(C)C)C3)=CC=2)C1)=O)=O)=O)(C)(C)C.[CH3:85][C:86]1[O:90][C:89]([C@@H:91]([NH:99]C(=O)OC(C)(C)C)[CH2:92][C:93]2[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=2)=[N:88][N:87]=1>>[CH3:85][C:86]1[O:90][C:89]([C@@H:91]([NH2:99])[CH2:92][C:93]2[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=2)=[N:88][N:87]=1
Reactant: Cc1nnc([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)o1
Agent: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Product: Cc1nnc([C@@H](N)Cc2ccccc2)o1
Yield: 51.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound B of Example 78, (S)-tert-butyl (1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-phenylethyl)carbamate (130 mg, 0.43 mmol) was converted to the title compound (45 mg, 52% over 2 steps) after preparative HPLC. 1H NMR (CDCl3) δ 7.38-7.14 (m, 1H), 4.43 (dd, J=8.4, 5.5 Hz, 1H), 3.27 (dd, J=13.6, 5.3 Hz, 1H), 3.04 (dd, J=13.6, 8.4 Hz, 1H), 2.53 (s, 3H); MS (ESI+) m/z 204.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[O:4]>[Ni].CO>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([N:2]([CH3:18])[CH3:1])=[O:4])=[C:6]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:7]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Ni]
Solvent: CO
Product: CN(C)C(=O)c1ccc(N)cc1S(N)(=O)=O
Yield: 98.8 %

Procedure:
1 g of moist Raney nickel is added to a solution of 12.5 g of 2-dimethylaminocarbonyl-5-nitrobenzenesulfonamide in 250 ml of methanol, and thorough mixing is carried out at 60° C. under a hydrogen pressure of 50 bar. After the end of uptake of hydrogen, the catalyst is separated off and the filtrate is concentrated, giving 11.0 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]1.Br[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:18]2[C:22](=[O:23])[N:21]([CH:24]([F:26])[F:25])[C:20]([CH3:27])=[N:19]2)=[CH:4][C:5]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:12][C:11]=1[Cl:17]
Reactant: Cc1nn(-c2cc(Oc3ccc(O)cc3Cl)c(Cl)cc2Cl)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2cc(-n3nc(C)n(C(F)F)c3=O)c(Cl)cc2Cl)c(Cl)c1
Yield: 51.5 %

Procedure:
In a manner similar to Step D of Example 1, the reaction of 1.3 g (0.0029 mole) of 1-[2,4-dichloro-5-(2-chloro-4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one with 0.73 g (0.0044 mole) of methyl 2-bromopropionate and 0.60 g (0.0044 mole) of potassium carbonate in 60 ml of methyl ethyl ketone yielded 0.78 g of methyl 2-[4-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro -3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]-3-chlorophenoxy]propionate as an oil, compound 150 of Table 1.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:34]=[CH:33][C:20]([CH2:21][N:22]5[CH2:25][CH:24]([C:26]([O:28]C(C)(C)C)=[O:27])[CH2:23]5)=[CH:19][CH:18]=4)[N:13]=3)[C:8]=2[C:35]([F:38])([F:37])[F:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:34]=[CH:33][C:20]([CH2:21][N:22]5[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]5)=[CH:19][CH:18]=4)[N:13]=3)[C:8]=2[C:35]([F:36])([F:37])[F:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl 1-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (293 mg, 0.556 mmol) in trifluoroacetic acid (4 mL) was allowed to stand at room temperature for 1.5 h. The volatiles were removed under reduced pressure, and the residue was suspended in water (5 ml). The pH was adjusted to −4 with a 1N aqueous solution of sodium hydroxide with stirring. The resulting thick suspension was stirred at room temperature for 1 hr. The precipitate was collected by vacuum filtration and dried well under reduced pressure. The compound was suspended in methanol and stirred at room temperature for 18 hr. The product was collected by vacuum filtration, washed with methanol, and dried well under reduced pressure to afford 1-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (194 mg, 0.412 mmol, 74.1% yield) as a white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:36](O)[CH:37]([CH3:39])[CH3:38].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:36][CH:37]([CH3:39])[CH3:38])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred suspension of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added isobutanol (0.03 mL, 0.33 mmol), and NaH (0.0132 g, 0.33 mmol). The resulting solution was stirred under nitrogen for 1 hour. The reaction was poured into H2O and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The crude solid was purified using flash chromatography (SiO2, 2:1 hexanes:ethyl acetate) to provide the desired product (yield: 0.1088 g 76%). mp 166-169° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.84 (m, 1H), 3.29 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.51-7.63 (m, 3H), 7.76 (m, 1H), 7.92 (m, 2H), 8.07 (m, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 433 (M+H)+, 450 (M+NH4)+. Anal. calc. for C21H21ClN2O4S: C, 57.07; H, 5.01; N, 6.33. Found: C, 57.06; H, 4.78; N, 6.13.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]1[O:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:20][N:21]=1.[C:28]([C:35]1[NH:36][CH:37]=[CH:38][N:39]=1)([C:30]1NC=CN=1)=O.CCN(C(C)C)C(C)C.N1CCCNCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C1C=CN=CC=1)C.CS(C)=O.CCOC(C)=O.O.CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:39]3[CH2:30][CH2:28][CH2:35][NH:36][CH2:37][CH2:38]3)=[O:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]1[O:18][C:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:20][N:21]=1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1-c1nnc(-c2ccccc2)o1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: C1CNCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(-c2ccc(C(=O)N3CCCNCC3)cc2)cc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A solution of 4-(6-amino-5-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)benzoic acid (75.4 mg, 0.2104 mmol), carbonyl diimidazole (68.23 mg, 0.4208 mmol), DMAP (2.570 mg, 0.02104 mmol) and DIPEA (81.58 mg, 109.9 μL 0.6312 mmol) in DMSO (1.282 mL) was treated with 1,4-diazepane (63.22 mg, 0.6312 mmol) and the resulting solution stirred at ambient temperature for 16 hours. The reaction was treated with TBTU (67.56 mg, 0.2104 mmol) followed by 1,4-diazepane (63.22 mg, 0.6312 mmol) and DMF (1.282 mL) and allowed to stir at 60° C. for a further 48 hours. The reaction was treated with further TBTU (135.12 mg, (0.4208 mmol) and heated at 60° C. for a further 5 hours. The reaction mixture was diluted with EtOAc/water and the two layers separated. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound (31 mg, 33% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.69 (s, 1H), 1.79 (s, 1H), 2.68 (s, 1H), 2.79-2.86 (m, 2H), 2.98 (t, J=4.9 Hz, 1H), 3.42 (dd, J=5.9, 12.8 Hz, 2H), 3.67 (d, J=5.3 Hz, 2H), 7.50 (dd, J=3.4, 7.9 Hz, 2H), 7.56 (s, 2H), 7.63-7.71 (m, 3H), 7.84 (q, J=3.9 Hz, 2H), 8.25-8.27 (m, 3H), 8.59 (d, J=2.3 Hz, 1H) and 8.66 (d, J=2.2 Hz, 1H) ppm; MS (ES+) 441.2.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[O:19][CH:17]1[CH3:18]>[OH-].[Na+]>[CH2:1]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH:17]([OH:19])[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)cc1Cc1ccccc1
Reactant: CC1CO1
Agent: [Na+]
Agent: [OH-]
Product: CC(O)COc1ccc(Cl)cc1Cc1ccccc1

Procedure:
2-Benzyl-4-chlorophenol (43.7 parts) is propoxylated with propylene oxide (12.6 parts) using sodium hydroxide (0.2 part) as catalyst at 145° C. in a manner similar to that used in Example 10 to give 1-(2-benzyl-4-chlorophenoxy)propan-2-ol (16.3 parts)
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[Na+].Cl[S:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=1)(=[O:32])=[O:31]>C(O)C(N)(CO)CO.C1COCC1>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][S:30]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[C:35]([OH:42])[CH:34]=3)(=[O:32])=[O:31])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4ccc(C(=O)O)c(O)c4)c(C(C)C)c3)c2c1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
At ambient temperature, to a stirred suspension of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenol (0.306 g, 0.744 mmol) in 0.05 M Tris buffer pH 9: THF (10:3, 3.56 mL, 0.2 M) was added 2.5N NaOH (0.285 mL, 0.713 mmol) followed by a minimal amount of THF to form a solution. After 0.5 h, the reaction was cooled to 5° C. To the reaction was added dropwise, a solution of 4-chlorosulphonyl-2-hydroxybenzoic acid (0.338 g, 1.43 mmol) in THF (2.85 mL, 0.5M) while maintaining the pH at 10 with the simultaneous addition of 2N NaOH. After the addition was completed, the reaction was allowed to warm to ambient temperature and stirred for 1.5 h. At 5° C. additional 4-chlorosulphonyl-2-hydroxybenzoic acid (0.338 g, 1.43 mmol) in THF (2.85 mL, 0.5 M) was added in the exact same manner as above and the reaction was stirred for 1.5 h. The reaction was quenched with 2N HCl (40 mL) and extracted with EtOAc. The combined organic extracts were washed with 2N HCl (3×), dried (MgSO4) and concentrated. Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil eluting with a 15 & 25% EtOAc/Hexane step gradient gave 0.294 g, (66%) of the title compound as a yellow solid, mp >225° C.; 1H NMR (DMSO-d6): δ 0.96 (d, 3 H), 1.02 (d, 3 H), 1.48 (s, 3 H), 2.50 (s, 3 H), 3.08 (heptet, 1 H), 7.26-7.39 (m, 5 H), 7.43 (dd, 1 H), 7.50 (t, 1 H), 7.66 (t, 1 H), 8.05 (d, 1 H), 8.21 (d, 1 H). IR (KBr) 3425, 2950, 1675, 1400 and 1190 cm-1. mass spectrum (-ESI), m/z 623/625 (M-H). Anal. Calcd. for C30H25BrO6S2 : C, 57.60; H, 4.03; N, 0.00. Found: C, 57.88; H, 4.29 N, 0.09.
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[O:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][C:17]#[CH:18].[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][C:28]#[C:29][CH2:30]I.S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][C:28]#[C:29][CH2:30][C:18]#[C:17][CH2:16][C:15]#[C:14][CH2:13][C:12]#[C:11][CH2:10][O:9][C:8]1[CH:19]=[CH:20][CH:21]=[C:6]([CH3:5])[CH:7]=1
Reactant: C#CCC#CCC#CCOc1cccc(C)c1
Reactant: COC(=O)CCCC#CCI
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCC#CCC#CCC#CCC#CCOc1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.61 ml (751 mg, 5.6 mmol) of 3.6N ethylmagnesium bromide in ether was added dropwise, under argon to a solution of 1.34 g (6 mmol) of 9-(m-methylphenoxy)-1,4,7-nonatriyne in 20 ml of anhydrous tetrahydrofuran. The temperature was maintained at 0° C. The reaction mixture was stirred for one hour further at 0° C., then allowed to warm to room temperature, and then 50 mg of cuprous cyanide wasadded. The mixture was stirred for 20 minutes, heated to 40° C. and then 1 g (3.75 mmol) of 7-iodo-5-heptynoic acid methyl ester was added. The resulting mixture was stirred during 4 hours at 40° C. The reaction mixture was then poured into 60 ml of 1N sulfuric acid and ice and the product extracted with ether (3×100 ml). The combined organic extract was concentrated to about 1/5 its original volume and washed several times with EDTA and water, dried over sodium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on 75 g of silica gel, using hexane:ethyl acetate (85:15) as eluant, to obtain 16-(m-methylphenoxy)hexadeca-5,8,11,14-tetraynoic acid methyl ester, as an oil. The product was stored in dry ice.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19]C(OC)=O)[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:59]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[NH2:59][CH2:19][C:14]1[C:15]2[CH2:16][S:17][N:18]=[C:9]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]3=[N:26][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:24]=[C:12]([C:11]=23)[CH:13]=1
Reactant: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1c(C)cnc(Cn2nc3cc(CN)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture composed of methyl {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetate of Example 111 (121 mg), diphenylphosphoryl azide (64 μl), triethylamine (69 μl) and benzene (2 ml) was heated with stirring at a bath temperature of 55° C. for two hours. The reaction mixture was concentrated under reduced pressure. Tetrahydrofuran (8 ml) and a 1 N sodium hydroxide solution (4 ml) were added to the resulting residue, and the mixture was heated with stirring at a bath temperature of 55° C. for one hour. A 0.2 N sodium hydroxide solution was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (41 mg) as a brown oil. Although the product contained impurities, it was directly used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:19][NH2:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:20][CH3:19])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: CN
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.8 %

Procedure:
To a solution of 2,4-dichloro-5-nitrobenzoic acid (8 g, 33.9 mmol) in toluene (200 ml) was added thionyl chloride (12.4 ml, 169 mmol) at room temperature. The mixture was stirred at 80° C. for 5 h. The solvent was removed and the residue was dissolved with tetrahydrofurane (60 ml). The mixture was added 40% methylamine (1.4 ml, 33.9 mmol) at 0° C. and the mixture was stirred at room temperature for 2.5 h. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (100 ml), brine (100 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2:1/1:1/1:2) to afford 5.3 g (63%) of the title compound as pale yellow solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7](=[O:18])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(O)c2cccnc2n(C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)c2cccnc2n(C)c1=O

Procedure:
A stirred mixture of 1.7 g. of 4-hydroxy-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 25 ml. of phosphorus oxychloride was heated under reflux for 2 hours. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured into 100 ml. of ice water. The precipitate which formed was collected, air dried and a small amount of the 1.9 g. was recrystallized from heptane twice to give the analytical sample of the title compound, m.p. 132°-135° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:12]=[N:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:36]1[CH2:41][CH2:40][N:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+].C12(PC34CC(CC3)CC4)CC(CC1)CC2>[Pd+2]>[CH2:45]([S:42]([N:39]1[CH2:38][CH2:37][CH:36]([C:27]2[C:26]3[C:30](=[C:31]([C:33]([NH2:35])=[O:34])[CH:32]=[C:24]([C:9]4[CH:14]=[N:13][CH:12]=[C:11]([CH2:15][N:16]5[CH2:17][CH2:18][O:19][CH2:20][CH2:21]5)[CH:10]=4)[CH:25]=3)[NH:29][CH:28]=2)[CH2:41][CH2:40]1)(=[O:44])=[O:43])[CH3:46]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cncc(CN3CCOCC3)c2)OC1(C)C
Agent: [Pd+2]
Agent: C1CC2(PC34CCC(CC3)C4)CCC1C2
Agent: O=C([O-])[O-]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN5CCOCC5)c4)cc23)CC1
Yield: 43 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), morpholine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 28 mg of crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine. The crude 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}morpholine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl)-dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 15.8 mg of the title compound (43%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11].CC(C)([O-])C.[K+]>COCCOCCOC>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Temperature: 38 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 4-hydroxybenzyl alcohol (100.08 grams, 806 mmol), 2-nitropropane (400 mL, 4.45 mol) and diglyme (800 mL) was heated to 38° C. Potassium t-butoxide (45.29 grams, 403.6 mmol) was added, and the mixture was heated to reflux at 132° C. with a Dean-Stark trap. Water began collecting in the trap, and continued at a high rate for approximately 1.5 hours. When water collection slowed (around 2.5 hours), portions of solvent (30-40 mL each) were removed every thirty minutes. During the water collection and solvent removal, the temperature rose from 132° C. to 149° C. After 4 hours less than 1% of the 4-hydroxybenzyl alcohol remained by HPLC analysis. The heating mantle was removed, and the reaction mixture was allowed to cool. When the temperature was 100° C. water (200 mL) was added, and the solution was allowed to cool to room temperature. Solvent was removed on a rotary evaporator under vacuum until 593 grams of solution remained. Water (500 mL) and ethyl acetate (500 mL) were added and the layers were separated (layer separation was poor, but addition of 20% aqueous NaCl was ineffectual). The aqueous layer was extracted with ethyl acetate (200 mL), and the combined organic layers were extracted with 1N HCl (500 mL) and water (300 mL). The organic layer was distilled in vacuo to 261 g of oil to which ethyl acetate was added (160 mL). Heptane (3.4 L) was added rapidly with vigorous stirring for 30 minutes, and the product crystallized to yield a beige solid (112.36 grams, 71% yield, >98% purity by HPLC analysis). Another crop of crystals may be obtained from the filtrate by concentrating and filtering the solids, or by concentrating—and adding heptane to crystallize.