Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])/[CH:29]=[CH:30]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(F)(F)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 59, Step 1, using 1-{4′-[4-(2,2-difluoro-1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([O:28][CH3:29])[C:22]([O:30][CH3:31])=[CH:21]2.Cl.[N:33]([O-])=O.[Na+].O>C(O)(=O)C>[CH2:11]([O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[N:1]=[N:33][C:19]3[C:18]([C:3]=2[CH:4]=1)=[CH:27][CH:26]=[C:25]1[CH:24]=[C:23]([O:28][CH3:29])[C:22]([O:30][CH3:31])=[CH:21][C:20]=31)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1cc2ccc(-c3cc(OCc4ccccc4)c(OC)cc3N)cc2cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ccc3c4cc(OCc5ccccc5)c(OC)cc4nnc3c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
6-(2-Amino-5-benzyloxy-4-methoxyphenyl)-2,3-dimethoxy-naphthalene 41 (35 mg, 0.084 mmol) was dissolved in acetic acid (0.65 mL) and concentrated hydrochloric acid (0.13 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.052 g in 0.52 mL water). The reaction mixture was allowed to warm slowly to room temperature and left for 1 day. To the resulting red solution containing some precipitate was added 50 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried using anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 20:80 hexanes:ethyl acetate to give the pure 42 (24 mg) in 67% yield; mp 244-246° C.; IR (KBr) 2935, 1621, 1507, 1466, 1307, 1269, 1234, 1206, 1168 cm−1; 1H NMR (CDCl3) δ4.07 (3H, s), 4.14 (3H, s), 4.21 (3H, s), 5.40 (2H, s), 7.25 (1H, s), 7.37-7.60 (5H, m), 7.91 (1H, d, J=9.0), 7.97 (1H, s), 8.01 (1H, d, J=9.0), 9.11 (1H, s); 13C NMR δ56.48, 56.86, 56.91, 71.64, 101.69, 104.43, 107.82, 109.58, 116.84, 118.19, 118.81, 126.95, 127.97, 128.34, 128.90, 129.34, 131.51, 136.31, 141.61, 144.52, 151.00, 151.14, 152.31, 152.93; HRMS (EI) calcd for C26H22N2O4 m/z: 426.1580; found: 426.1577.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[C:14](=[O:30])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH3:29])[CH2:17]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=3)[CH2:9][CH2:10]2)=[O:30])[CH2:17][C@H:18]1[CH3:29])=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(C(=O)O)cc32)CCN1C(=O)OC(C)(C)C
Yield: 94.6 %

Procedure:
1-[2-((R)-4-tert-Butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (690 mg, 1.65 mmol) was dissolved in THF/MeOH/H2O (3.3/3.3/1.7 mL) and sodium hydroxide (331 mg, 8.27 mmol) was added. The reaction was stirred for 18 h and neutralised with 2 M hydrochloric acid (4.1 mL). The solvent was removed in vacuo and the residue azeoptroped with MeOH to dryness, to give the title compound (630 mg, 95%) as a red/pink solid. 1H NMR (Me-d3-OD): 8.76 (1H, s), 7.71 (1H, dd), 7.27 (1H, d), 4.39-4.28 (2H, m), 4.27-4.10 (1H, m), 3.83 (1H, d), 3.28-3.07 (3H, m), 2.93 (1H, d), 2.84 (1H, d), 2.33 (1H, dd), 2.26-2.08 (1H, m), 1.47 (9H, s), 1.34-1.27 (3H, m).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)c(Cl)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2cc(Cl)c(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 13, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (90 mg, 34%). MS (ES): M/Z [M+H]=474. 1H NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 5.41-5.51 (m, 2H), 7.82-7.91 (m, 4H), 8.41 (br s, 2H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.94 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=O)[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN.[OH-].[K+]>C(O)CO>[Cl:1][C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2c(Cl)cccc2-c2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Clc1cccc2c1CCCCc1ccccc1-2
Yield: 90.6 %

Procedure:
The reaction of 9-chloro-5,6,7,8-tetrahydrodibenzo[a,c]-cycloocten-5-one (3.0 g, 0.015 mole), 85% hydrazine hydrate (4.5 g, 0.076 mole), potassium hydroxide (3.0 g, 0.046 mole) and ethylene glycol (39 ml) produced an oil. The oil was purified by column chromatography on silica gel, eluted with toluene to yield 4-chloro-5,6,7,8-tetrahydrodibenzo[a,c]cyclooctene as an oil (3.3 grams).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCCl>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1c(-c2ccccc2)oc2c(CN)cccc2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(CNC(=O)CCl)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.2 ml of chloracetyl chloride in 32 ml of 1,2-dichloroethane was added dropwise, under stirring at -5° C., to a mixture of 10 g of Intermediate XXIV and 5.5 ml of triethylamine in 80 ml of 1,2-dichloroethane. The reaction mixture was stirred at ambient temperature for 1 hour and then 150 ml of water was added. The phases were separated; the aqueous phase was extracted with 1,2-dichloroethane and the extracts were added to the organic phase which was then washed with a cold saturated solution of sodium bicarbonate, washed with water, dried on anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from ethanol to give 10.7 g of the title compound, m.p. 152°-155° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[S:33][CH:34]=[CH:35][N:36]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: Brc1nccs1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nccs2)cc1[N+](=O)[O-]
Yield: 26.2 %

Procedure:
Prepared from (2-nitro-4-tributylstannanyl-phenyl)-carbamic acid tert.-butyl ester (Example D2) (1.0 g, 1.9 mmol) and 2-bromothiazole (0.56 mL, 6.27 mmol) according to the general procedure E. Obtained as a yellow solid (160 mg). MS (EI) 321 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].[CH3:20]I>C(=O)([O-])[O-].[Ag+2].C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([O:18][CH3:20])[C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6]
Reactant: CI
Reactant: Cc1cc(Oc2cc(Cl)cc(C#N)c2)c(Cl)c(=O)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1nc(C)cc(Oc2cc(Cl)cc(C#N)c2)c1Cl
Temperature: 50 °C

Procedure:
Compound 3-4 (2.45 g; 8.32 mmol), methyl iodide (1.573 mL; 25.2 mmol), silver carbonate (3.28 g; 11.89 mmol) and chloroform (100 mL) were added to a sealed vessel. The contents of the sealed vessel were heated at 50° C. for 3 hours in the absence of light. The reaction was cooled to room temperature, the insoluble material filtered off, and the filtrate concentrated in vacuo. The crude material was purified via silica gel chromatography (0-10% EtOAc in hexane) to give the title compound. MS M+1=308.9. 1H NMR (CDCl3): 2.42 (s, 3H), 4.05 (s, 3H), 6.36 (s, 1), 7.16 (m, 1H), 7.24 (m, 1H), 7.44 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[N:10]=[C:9]1[C@H:21]([NH2:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([CH2:29][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:31][O:32][CH3:33])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[N:10]=[C:9]1[C@H:21]([NH:26][CH2:27][CH2:29][C@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:31][O:32][CH3:33])[C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@H](CC=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[C@@H](N)c1nc(-c2cc(F)ccc2F)cn1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC[C@H](CCN[C@@H](c1nc(-c2cc(F)ccc2F)cn1Cc1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (R)-1-(1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine (1 eq) in dichloromethane was added tert-butyl (S)-1-formyl-3-methoxypropan-2-ylcarbamate (1.5 eq) and acetic acid (1 eq). The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxy borohydride (2 eq) was added at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. Solvent was concentrated and crude was partitioned between ethyl acetate and satd. sodium bicarbonate. The organic layer was washed with water, brine and dried over sodium sulfate. Purification by silica gel chromatography (25% EtOAc/Hexane) provide pure product as a white foamy solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[C:23]([CH2:28][NH2:29])=[N:24][CH:25]=[CH:26][CH:27]=1>CCCCO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:29][CH2:28][C:23]2[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cccnc1CN
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CNc1nc(F)nc2[nH]cnc12
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.3 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (3-methylpyridin-2-yl)methanamine (0.36 g, 2.95 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.3 g (51%). δH (CDCl3, 500 MHz) 2.35 (3 H, s, CH3), 4.71 (3 H, m, NH and NHCH2), 7.24 (1 H, s, br, ArH), 7.63 (1 H, s, br, ArH), 8.28 (1 H, s, br, ArH), 8.38 (1 H, s, br, ArH); δC (CDCl3, 500 MHz) 161.03 (C), 158.49 (C), 154.77 (C), 152.16 (C), 144.86 (CH), 137.53 (CH), 137.14 (CH), 130.67 (C), 121.58 (CH), 118.73 (C), 42.87 (CH2), 18.16 (CH3); m/z 259.3 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:12]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].[C:37]([O-:42])(=[O:41])[C:38]([O-:40])=[O:39]>N1C=CC=CC=1>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:30](=[O:32])[CH3:31])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:12]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C([O-])C(=O)[O-]
Reactant: CCN(CC)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Product: O=C(O)C(=O)O

Procedure:
A mixture of 0.67 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(diethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 7 ml of acetic anhydride and 2 drops of pyridine is treated in the same manner as described in Example 16. The crude product is converted into its oxalate and recrystallized from ethanol. 0.634 g of (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(diethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one oxalate is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:16]2[C:15](=[O:18])[N:4]3[N:5]=[CH:6][C:7]([C:8]4[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=4)=[C:2]([Cl:1])[C:3]3=[N:17]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 55 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a stirring suspension of 8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.12 g, 4.0 mmol) and 4-(trifluoromethyl)benzyl bromide (1.24 g, 5.2 mmol) in DMF (15 mL) at RT under argon was added K2CO3 (0.83 g, 5.2 mmol). The resulting mixture was heated at 55° C. for 2 h. After 2 h, HPLC/MS analysis indicated the reaction was complete. The reaction mixture was cooled to RT and EtOAc (100 mL) was added. The resulting mixture was washed with saturated NaCl (50 mL×2). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum with co-evaporation of toluene (10 mL×2) to obtain a dark yellow solid. This crude product was washed with MeOH (10 mL×2), then dried under vacuum at room temperature for 3 h to obtain the title compound, 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1.3 g, 74%) as a yellow solid. MS [M+H]+ 439; HPLC retention time=3.92 min; 1HNMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.45-7.61 (m, 8H), 5.32 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](/[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O:16][C:15](=[O:17])/[CH:14]=[CH:13]/[CH:12]=[C:11](/[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
As in Example 115, (E,E)-5-(3,4-dimethoxyphenyl)-2,4-decadienoic acid (3.08 g) and 4-nitrophenol (2.75 g) in 20 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (2.11 g). The mixture was stirred at room temperature for 3 days and after the usual work up, crystallization of the crude ester from 2-propanol-hexane gave 2.98 g of (E,E)-5-(3,4-dimethoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 95°-96.5° C.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:14][CH:15]=[CH2:16]>[Cu]Cl.N1C=CC=CC=1>[CH2:20]([O:19][C:18]([NH:17][C:13]1[C:2]2[C:1](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[C:3]=2[CH:16]=[CH:15][CH:14]=1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: C=CC=CNC(=O)OCc1ccccc1
Agent: Cl[Cu]
Solvent: c1ccncc1
Product: O=C(Nc1cccc2c1C(=O)c1ccccc1C2=O)OCc1ccccc1
Yield: 89.6 %

Procedure:
0.79 g of 1,4-naphthoquinone, 1.07 g of benzyl N-butadienylcarbamate, 25 mg of copper(I) chloride and 25 ml of pyridine were stirred at 25° C. for 30 hours under a gentle stream of air and the solution was then concentrated in vacuo. The residue was taken up in chloroform, the solution was extracted with 2N hydrochloric acid and the organic phase was concentrated in vacuo. 1.60 g of 1-benzyloxycarbonylaminoanthraquinone (83% pure; 75% of theory) were obtained.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1([C:15]([NH:17][C@H:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]2=[O:35])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)([O:6]CC)=[O:5])C.Br[Si](C)(C)C.C([N:43](CC)CC)C>ClCCl.CC(C)=O>[P:4]([CH2:9][C:10]1([C:15]([NH:17][C@H:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]2=[O:35])=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14]1)([OH:5])([OH:6])=[O:3].[CH3:24][CH:23]([NH3+:43])[C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:21]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)C2(CP(=O)(OCC)OCC)CCCC2)CCc2ccccc21
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Br
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC([NH3+])c1ccccc1
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)C2(CP(=O)(O)O)CCCC2)CCc2ccccc21

Procedure:
1.3 g of ethyl (3S)-3-(1-diethylphosphono-methylcyclopentane-1-carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 12) were dissolved in 13 ml of dry dichloromethane under a nitrogen atmosphere. 0.5 ml of bromotrimethylsilane and 0.4 ml of triethylamine were added with ice-cooling and the mixture was stirred over night. Excess solvent was stripped off in vacuo, and the residue was stirred in aqueous acetone for 15 minutes. The residue which remained after evaporation of the solvent was taken up in MTBE to which a little dichloromethane had been added and treated with 0.53 g of S-(-)-α-methylbenzylamine. The precipitated solid was recryatallized once from ethanol, the title compound being obtained as the α-methylbenzylammonium salt of m.p.=210-213° C. IR=2940, 1750, 1650, 1200, 1045 cm-1 (KBr); [α]D20 32 -141.0° (c=0.2 in methanol).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15]([OH:17])=[O:16])[CH2:3]1>ClCCl>[O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15]([O:17][C:4]([CH3:15])([CH3:5])[CH3:3])=[O:16])[CH2:3]1
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)O)CC1=O
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Yield: 128 %

Procedure:
To a dichloromethane suspension (10 L) of 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid (1165 g, 4.994 mol) was added o-tert-butyl-N,N′-diisopropylurea (3020 g, 15.00 mol) at room temperature with being stirred with a blade. After increase of inner temperature and beginning of reflux were observed, the solution was cooled in an ice water bath. The reaction solution was cooled to room temperature, subsequently the ice water bath was removed and the solution was stirred for an hour, and then with heating the solution up to 40° C. for 3 hours. After that, this reaction solution was cooled in an ice water bath and stirred for an hour. Subsequently, an insoluble material was removed by filtration, and the filtrate was dried under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (silica gel: 4 kg; eluant: hexane/ethyl acetate in the ratio of 3:1) to obtain 925.2 g (64%) of the title compound (mixture with 3-position isomer) as a light yellow syrup. Each diastereomer derived from 3-position of pyrrolidine was able to be fractionated easily; however, the compound was used without fractionating the diastereomers because the subsequent step is a reaction involving epimerization.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][O:14][CH2:15][CH2:16][Br:17]>>[BrH:17].[CH3:13][O:14][CH2:15][CH2:16][N:9]1[CH:8]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[S:11][C:10]1=[NH:12]
Reactant: COCCBr
Reactant: Nc1ncc(C2CCOCC2)s1
Product: Br
Product: COCCn1cc(C2CCOCC2)sc1=N

Procedure:
A mixture of Example 138A and commercially available 2-bromoethyl methyl ether (Aldrich) was processed using the method described in Example 46A to afford the title compound. MS (ESI+) m/z 24.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.CC1(C)C(C)(C)OB(C(C2C=CC([C:70]([F:73])([F:72])[F:71])=CC=2)=C)O1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:70]([F:73])([F:72])[F:71])=[CH:27][CH:26]=2)=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccc(C(F)(F)F)cc1
Reactant: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: C=C(c1ccc(C(F)(F)F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 48 %

Procedure:
Prepared according to the method for 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 4,4,5,5-tetramethyl-2-{1-[4-(trifluoromethyl)-phenyl]ethenyl}-1,3,2-dioxaborolane (Intermediate 66) in 48% yield.