Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:9](=[N:11][OH:12])[NH2:10])=[N:7][CH:8]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](Cl)=O>>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[O:12][N:11]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:8][N:7]=2)[N:10]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NC(=NO)c1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(-c2noc(-c3sccc3Cl)n2)nc1

Procedure:
The title compound was prepared from 5-trifluoromethyl-pyridine-2-amidoxime (516 mg, 2.52 mmol) and 3-chloro-thiophene-2-carbonyl chloride (455 mg, 2.51 mmol) similar to Example 16, and yielded 764 mg (92%) of off-white solid. 1H NMR (CDCl3): 9.09 (m, 1H), 8.36 (d, J=8.24 Hz, 1H), 8.14 (m, 1H), 7.66 (d, J=5.22 Hz, 1H), 7.16 (d, J=5.49 Hz, 1H).
Reaction SMILES: C(OCC)(=O)C.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-:21]#[N:22].[K+]>O>[OH:20][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:21]#[N:22]
Reactant: [C-]#N
Reactant: O=CCCCCCCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A two-phase mixture of ethyl acetate (30 mL) and water (35 mL) containing 7-phenylheptanal (5.2 g) and KCN (7.1 g) was stirred vigorously at room temperature for 24 h. The layers were separated and the aqueous phase was washed with water, dried (Na2SO4) and concentrated to yield 2-hydroxy-8-phenyloctanenitrile as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH:25]([NH:28][CH3:29])([CH3:27])[CH3:26]>>[CH:25]([N:28]([CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)[CH3:29])([CH3:27])[CH3:26]
Reactant: CNC(C)C
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Product: CC(C)N(C)Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1

Procedure:
This compound was prepared according to the method described in example 8758 step (b) employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and N-isopropyl-N-methylamine to provide the desired compound as a yellow solid. MS m/z; 391.0 (M+1).
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](Cl)=[C:24]([Cl:29])[N:25]=[N:26][C:27]=2[CH3:28])=[CH:18][CH:17]=1>C(OCC)(=O)C>[Cl:29][C:24]1[N:25]=[N:26][C:27]([CH3:28])=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)[C:23]=1[N:10]1[C:9]([CH3:8])=[CH:13][C:12]([CH3:14])=[N:11]1
Reactant: Cc1nnc(Cl)c(Cl)c1-c1ccc(Cl)cc1
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29 mg of sodium hydride (55% oil dispersion) was added to tetrahydrofuran. Into this, a tetrahydrofuran solution of 3,5-dimethylpyrazole was added dropwise. The resultant mixture was added dropwise into 0.20 g of 5-(4-chloro-phenyl)-3,4-dichloro-6-methylpyridazine while cooling with ice. The mixture was stirred overnight at room temperature. To the reaction mixture was added ethyl acetate, and the mixture was washed with dilute hydrochloric acid water and brine sequentially. The organic layer was dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.27 g of the resultant residue was subjected to silica gel column chromatography, to obtain 50 mg of 3-chloro-5-(4-chlorophenyl)-4-(3,5-dimethyl-1-pyrazolyl)-6-m ethylpyridazine (hereinafter, described as compound (2) of the present invention) and 59 mg of 4-chloro-5-(4-chlorophenyl)-3-(3,5-dimethyl-1-pyrazolyl)-6-m ethylpyridazine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([F:9])[C:5]([CH3:8])([OH:7])[CH3:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.O>CN(C)C=O>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:7][C:5]([CH3:8])([CH3:6])[C:4]([F:10])([F:9])[F:3])[CH:14]=1
Reactant: CC(C)(O)C(F)(F)F
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(OCc1cccc(Cl)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a suspension cooled to 0° C. of sodium hydride (126 mg, 60 wt. % oil dispersion) in N,N-dimethylformamide (5 ml) was added dropwise, 1,1,1-trifluoro-2-methylpropan-2-ol (320 μL) under argon atmosphere, and the mixture was stirred for 15 minutes. To this reaction mixture was added dropwise 1-bromomethyl-3-chlorobenzene (320 μL), and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 40/1) to give the titled compound (389 mg).
Reaction SMILES: Br[C:2]1[C:3]2[S:9][CH:8]=[C:7]([Br:10])[C:4]=2[S:5][CH:6]=1.[C:11]([O:15][C:16]([N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(N1CCC[C@H]1C1NC(C2SC3C=C(C4C=CC(C5NC([C@@H]6CCCN6C(=O)[C@@H](NC(OC)=O)C(C)C)=NC=5)=CC=4)SC=3C=2)=CN=1)=O)(C)(C)C>>[C:11]([O:15][C:16]([N:18]1[CH:22]=[C:21]([C:2]2[C:3]3[S:9][CH:8]=[C:7]([Br:10])[C:4]=3[S:5][CH:6]=2)[N:20]=[C:19]1[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1csc2c(Br)csc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1C(=O)OC(C)(C)C
Agent: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4s3)cc2)[nH]1)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2csc3c(Br)csc23)cn1C(=O)OC(C)(C)C

Procedure:
Compound 76 was synthesized from 3,6-dibromothieno[3,2,b]thiophene (6.71 mmol) and compound 61 (6.71 mmol), following the procedure as described for compound 63 to give compound 76 as a yellow crystal. MS (ESI, EI+) m/z=554-556 (MH+).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH3:44]I>C1COCC1.O>[CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:20][CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
A solution of 6.0 grams (0.01 mole) (±)-1-S-hexadecyl-3-O-tritylthioglycerol in 250 milliliters of THF was added to a slurry of 0.4 grams (0.014 mole) 80% NaH (oil dispersion) in 50 milliliters of THF and the reaction mixture stirred at room temperature for one hour. Then 1.4 gram (0.13 mole) of CH3I was added and the reaction allowed to proceed at room temperature for 24 hours. The reaction mixture was then diluted with 300 milliliters of distilled water and extracted twice with 200 milliliter portions of ether. The nonaqueous extracts were combined, dried over anhydrous sodium sulfate, filtered and removed in vacuo to provide 6.0 grams of crude product as an oil. 1H-NMR (CDCl3): delta, 0.7-1.7[m, 31H, (CH2)14CH3 ], 2.3-2.8(m, 4H, CH2 --S--CH2), 3.25(m, 5H, CH3O, CH--CH2 --O), 3.6-4.0(m, 1H, CH), 7.6-7.0[m, 15H, C(C6H5)3 ].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9](Br)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1Br.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:14][CH3:15])[C:9]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:24]1[S:23][CH:22]=[CH:26][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1c(Br)ccc2c(OC)c(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1c(-c2cccs2)ccc2c(OC)c(-c3cccs3)ccc12
Yield: 95 %

Procedure:
1,5-Dimethoxy-2,6-dibromonaphthalene (1.00 g., 0.0029 mol.) and 2-(tributylstannyl)thiophene (4.314 g., 0.0116 mol.) were dissolved in 100 mL dry toluene in argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlenk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 300 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2:petroleum ether (1:5), the desired product was obtained as a light yellow solid. Yield: 95%. M. p. 225-228° C. Anal. Calcd. for C20H16O2S2: C, 68.15%; H, 4.58%; S, 18.19%. Found: C, 67.98%; H, 4.53%; S, 18.03%. Mass spectrum: 351.84 (M+). 1 H-NMR (CDCl3; in ppm): 3.88 (s, 3H), 7.16 (dd, 2H), 7.43 (dd, 2H), 7.63 (dd, 2H), 7.83 (d, 2H, 9 Hz), 7.96 (d, 2H, 9 Hz). 13C-NMR (CDCl3; in ppm): 61.3, 119.0, 123.2, 125.7, 126.5, 126.6, 126.9, 129.2, 138.9, 152.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:18]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH:14]1[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1.[H-].[Na+].[C:36]([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH2:10][O:11][CH3:36])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]1[CH:14]([C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:15][CH2:16][CH2:17][CH:18]1[C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COC(=O)c1cc(CO)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCc1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(C(=O)OC)c1
Yield: 80 %

Procedure:
To a cold (0° C.) solution of 2-(3,3″-Dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-5-hydroxymethyl-benzoic acid methyl ester (0.290 g, 0.65 mmol) in THF (3 mL) was added a slurry of NaH (95% dry, 0.105 g, 4.38 mmol) in THF (10 mL) followed by neat Mel (0.40 mL, 6.43 mmol). The resultant mixture was stirred for 3 hours and treated with saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (50 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) gave COMPOUND 54 (239 mg, 80%) as a white solid. 1H NMR (CDCl3) δ 1.63-1.69 (m, 3H), 2.04-2.08 (m, 1H), 2.30-2.48 (m, 8H), 3.24 (s, 3H), 3.80 (s, 3H), 3.95 (s, 2H), 4.13 (d, 2H, J=11.7 Hz), 4.23 (s, 2H), 6.82 (dd, 2H, J=4.5, 7.5 Hz), 7.06-7.22 (m, 4H), 7.61 (d, 1H, J=7.8 Hz), 8.25 (d, 2H, J=4.5 Hz); 13C NMR (CDCl3) δ 19.31, 25.55, 28.99, 50.64, 51.97, 58.01, 66.99, 74.20, 122.01, 127.92, 128.41, 130.02, 131.46, 131.98, 134.84, 138.05, 143.31, 146.84, 159.84, 167.91; ES-MS m/z 460 (M+H). Anal. Calcd. For C28H33N3O3: C, 73.18; H, 7.24; N, 9.14. Found: C, 73.07; H, 7.15; N, 9.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)CC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(CC(C)C)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 33.1 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (635 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.82 ml) and 1-methyl-2-chloropyridinium iodide (1 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-4-methylpentanamide (455 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][N:19]([CH3:30])[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:18][N:19]([CH3:30])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)([O:17][CH3:34])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)CC2(OC)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To the compound (6.0 g) obtained in Example 12 in DMF (50 mL) was added 60% sodium hydride (0.65 g) under cooling with ice-water, followed by stirring at the same temperature for one hour. The reaction mixture was cooled to −40° C., and iodomethane (2.09 g) was added dropwise thereto over twenty minutes. After stirring at −40° C. for one hour and further stirring at −20 to −15° C. for four hours, the reaction mixture was left at −12° C. overnight. The reaction mixture was cooled to −20° C., was mixed with an ice water (100 mL) and was warmed to room temperature. After extracting with ethyl acetate, the organic layer was sequentially washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography [Chromatorex NH™] (eluent; hexane:ethyl acetate=3:1 to 1:1) to yield the titled compound (0.643 g) as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([CH2:48][O:47][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.552 g of 6-[3-[4-(diphenylmethoxy)piperidino]propoxy][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 3 ml of N,N-dimethylformamide; 0.200 g of potassium carbonate and 0.209 ml of chloromethyl pivalate were added, followed by stirring at room temperature for 20 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with siethyl ether-hexane (1:1), and dried, to yield 0.515 g of the title compound.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[O:11][C@@H:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[O:11][C@@H:10]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1C(=O)[C@@H](N)[C@@H](c2ccccc2)Oc2ccccc21

Procedure:
Methyl [(2R,3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-2-phenyl-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate (70a) (175 mg, 0.410 mmol) was dissolved in 5:1 (v/v) dichloromethane:trifluoroacetic acid (4 mL) and kept at ambient temperature for 30 min. The solution was evaporated and the residue was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic solution was dried and evaporated and the residue used immediately in the next step.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12]O)=[CH:6][C:5]=1[N:14]([CH3:16])[CH3:15].N12CCCN=C1CCCCC2.C1(P([N:43]=[N+:44]=[N-:45])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[C:7]([CH2:12][N:43]=[N+:44]=[N-:45])=[CH:6][C:5]=1[N:14]([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)c1cc(C#N)c(CO)cc1N(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)c(CN=[N+]=[N-])cc1N(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
After dissolving N1-methyl-5-cyano-2-(dimethylamino)-4-(hydroxymethyl)benzamide (849 mg, 3.6 mmol) in tetrahydrofuran (20 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.77 ml, 5.1 mmol) and diphenylphosphoryl azide (1.1 ml, 5.1 mmol) were added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (755 mg) as a faint yellow powder. (80% yield)
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[N:3]=[CH:2]1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:34])=CC=1>C1COCC1.O>[S:34]=[C:2]1[NH:3][C:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:5][NH:1]1
Reactant: N#Cc1ccc(-c2ccccc2Cc2c[nH]cn2)cc1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccccc2Cc2c[nH]c(=S)[nH]2)cc1
Reaction time: 16 h

Procedure:
A solution of 2′-(1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Intermediate D3) (0.36 g, 1.4 mmol) in THF (11 mL) and water (10 mL) was treated with NaHCO3 (1.2 g) at rt for 5 m. Phenyl chlorothionoformate (0.95 mL, 7.0 mmol) was added and stirring was continued for 16 h. The mixture was diluted with water (10 mL) and extracted with ether (4×15 mL). The organic portions were combined, dried over MgSO4, filtered and freed of solvent. The residue was dissolved in MeOH (15 mL) and treated with NEt3 (2.0 mL) for 18 h. The solvent was removed under vacuum and the product was washed on a glass frit with CH2Cl2 and pentane to give a solid 2′-(2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl)-biphenyl-4-carbonitrile (Compound 6) in 40% yield. 1H NMR (300 MHz, DMSO-d6): δ 11.8 (s, 1H), 11.6 (s, 1H), 7.92 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.44-7.19 (m, 4H), 6.14 (s, 1H), 3.63 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11](=[O:13])[CH3:12])[CH:3]=1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[N:20]([CH2:24][C:25](O)=O)[CH:21]=[CH:22][N:23]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH2:9]([N:8]1[C:7]2[CH:6]=[N:5][C:4]([C:11](=[O:13])[CH3:12])=[CH:3][C:2]=2[N:1]=[C:25]1[CH2:24][N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:15]1[S:14][CH:18]=[CH:17][N:16]=1)[CH3:10]
Reactant: CCNc1cnc(C(C)=O)cc1N
Reactant: O=C(O)Cn1ccnc1-c1nccs1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(C)=O)ncc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(4-amino-5-ethylamino-pyridin-2-yl)-ethanone (54 mg, 0.3 mmol), (2-thiazol-2-yl-imidazol-1-yl)-acetic acid (61 mg, 0.3 mmol), EDCI (60 mg, 0.3 mmol) and pyridine (2 mL) is stirred at room temperature for 72 hr and then poured into water. The aqueous layer is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is evaporated in vacuo and the residue is taken up in acetic acid (5 mL). The mixture is heated to reflux for 16 hr and saturated NaHCO3 solution is added to neutralize the reaction. The aqueous solution is extracted with ethyl acetate and the combined organic layers are dried over Na2SO4. Solvent is removed in vacuo and purification by preparative TLC provides the product as white solid. 1H NMR (CDCl3) δ 8.79 (d, 2H), 8.47 (d, 1H), 7.83 (d, 1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 6.39 (s, 2H), 4.02 (q, 2H), 2.77 (s, 3H), 1.86 (t, 3H). LRMS 353.2 (MH+).
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)/[C:6](O)=[O:7])(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:65][O:66][C:67](=[O:88])[C:68]1[C:73]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[CH:72][CH:71]=[CH:70][C:69]=1[O:82][CH2:83][CH2:84][CH2:85][CH2:86][NH2:87]>CN(C=O)C>[CH3:65][O:66][C:67](=[O:88])[C:68]1[C:73]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[CH:72][CH:71]=[CH:70][C:69]=1[O:82][CH2:83][CH2:84][CH2:85][CH2:86][NH:87][C:6](=[O:7])/[C:5](/[NH:4][C:1](=[O:3])[CH3:2])=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[NH:18][S:17]2(=[O:23])=[O:22])=[C:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:11]=1
Reactant: COC(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Reactant: CC(=O)N/C(=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OCCCCNC(=O)/C(=C\c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)NC(C)=O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (E)-2-acetylamino-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid (260 mg, 0.58 mmol) in DMF (10 mL) is added diisopropylethylamine (0.11 mL, 0.64 mmol) and HATU (243 mg, 0.64 mmol). The mixture is stirred at RT for 10 min then a solution of 2-(4-aminobutoxy)-6-benzyloxybenzoic acid methyl ester (Example 110, step C) (286 mg, 0.87 mmol) in DMF (1 mL) is added and stirring is continued for 18 h. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.