Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][Mg]Br.CCOCC.[Cl-].[NH4+]>CC(OC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:14])[CH:9]=1
Reactant: COc1cc(Cl)cc(C=O)c1OC
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: COc1cc(Cl)cc(C(C)O)c1OC
Temperature: 33 °C
Yield: 96 %

Procedure:
To a mixture of 5-chloro-2,3-dimethoxybenzaldehyde (339, 1.69 mol) in TBME (5.6 L) was added 3M methylmagnesium bromide in ether (660 mL, 1.98 mol) over 1 hour at 9 to 12° C. The mixture was warmed at 33° C. for 1 hour 20 minutes. There was significant starting material present so more methylmagnesium bromide was added (590 mL, 1.77 mol) over 1 hour 20 minutes with the reaction temperature at 33° C. The reaction was cooled to room temperature overnight and poured into ammonium chloride (20 wt %, 3 kg) over 5 minutes. The temperature rose from 11 to 28° C. The reaction flask was rinsed with ammonium chloride solution (500 mL) and TBME (250 mL). The layers were separated and the organic layer was concentrated to an orange yellow thick oil. Yield: 348 g (96% yield, 94% purity).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39]([CH:42]=[CH2:43])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH:39](/[CH:42]=[CH:43]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]3(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)C1
Product: CC(C)(C)OC(=O)N1CCC(/C=C/c2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)C1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 3-vinylpyrrolidine-1-carboxylic acid tert-butyl ester analogous to Example 62, step B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=O)OC(C)(C)C)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.O>C(O)=O.C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[CH3:19])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: COCCN(Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1)C(=O)OC(C)(C)C
Agent: C=O
Solvent: O
Solvent: O=CO
Product: COCCN(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 70 °C
Yield: 67.3 %

Procedure:
tert-Butyl (6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (95 mg, 0.22 mmol) was dissolved in 0.75 ml of formic acid and 1.4 ml of formalin. The reaction was heated at 70° C. for 4 hours. The reaction was cooled to room temperature, water was added and the aqueous layer was extracted with DCM. The aqueous layer was carefully basified with solid potassium carbonate and extracted 3 times with DCM. The crude product was purified by chromatography using a gradient of 5% to 15% methanol in DCM to give 50 mg (66.0%) of a white powder.
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.C(Cl)(=O)C.[CH3:12][O:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][CH:23]=[CH:22]3)=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:7][N:5]([CH2:4][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([O:18][C:17]3[CH:28]=[CH:29][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)[CH:20]=2)[NH:24][CH:23]=1)[CH3:6]
Reactant: COc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Reactant: CN(C)CN(C)C
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2ccc3[nH]cc(CN(C)C)c3c2)cc1
Reaction time: 0.33 h

Procedure:
N,N,N',N'-Tetramethyldiaminomethane (0.29 g, 0.39 mL, 2.82 mmol) was dissolved in CH2Cl2 (dry; 8.5 mL) and the stirred solution cooled in an ice-bath. Acetyl chloride (0.23 g, 0.21 mL, 2.95 mmol) was added dropwise (syringe) over 10 min, to give a white suspension. After stirring for a further 20 min. with cooling maintained, a solution of 5-(4-methoxyphenoxy)indole (0.5 g, 2.09 mmol) in CH2Cl2 (7.2 mL) was added dropwise, over 20 min. The cooling was removed and the resulting clear solution was stirred for 1 hr at room temperature. The solution was then diluted with CH2Cl2, washed with 10% aq. NaOH (2×) followed by saturated aqueous NACl and dried (MgSO4). Evaporation in vacuo gave 3-(N,N-dimethylaminomethyl)-5-(4-methoxyphenoxy)indole as a gum. This material was dissolved in DMF (dry; 7 mL) and potassium cyanide (0.52 g, 8.0 mmol) was added, followed by methyl iodide (1.19 g, 0.52 mL, 8.35 mmol). The mixture became cloudy and eventually opaque. After stirring at room temperature for 36 hr, water was added and the mixture was extracted with Et2O (2×). The combined organic layers were washed with H2O (2×) and then with saturated aqueous NaCl, dried (MgSO4) and evaporated to give an almost colourless gum. This was triturated with Et2O to give: 3-cyanomethyl-5-(4-methoxyphenoxy)indole as a virtually colourless solid, 0.334 g (57%).
Reaction SMILES: B.C1COCC1.[Cl:7][C:8]1[S:12][CH:11]=[C:10]([C:13]#[N:14])[CH:9]=1.Cl.O.CO>C1COCC1>[ClH:7].[Cl:7][C:8]1[S:12][CH:11]=[C:10]([CH2:13][NH2:14])[CH:9]=1
Reactant: N#Cc1csc(Cl)c1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NCc1csc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 312.2 %

Procedure:
To a pre-cooled (ice-water bath) solution of BH3.THF (3.4 eq, 11.8 mL) was added a solution of 5-chlorothiophene-3-carbonitrile (0.5 g, 3.48 mmol) in THF (11.5 ml). The reaction mixture was stirred for 4 hours at room temperature and subsequently 6 N HCl (17 ml) was added slowly followed by H2O/MeOH (17/114 mL). The reaction mixture was stirred overnight. Removal of the volatiles afforded the title product (1.0 g) as an off-white solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](Cl)=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:19][OH:20]>C(Cl)Cl>[CH3:19][O:20][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=C(Cl)c1ccc(CBr)cc1
Reactant: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.5 grams of alpha-bromo-p-toluoyl chloride in 100 ml of methylene chloride is added to a solution of 15.7 ml of triethylamine in 100 ml of methanol. The reaction mixture is stirred overnight at room temperature and then concentrated. The residue is dissolved in ether, washed with water and the ether evaporated to give the intermediate p-methoxycarbonylbenzyl bromide.
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH2:24][N:25]=[N+]=[N-])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Sn](Cl)Cl.[OH-].[Na+]>CO>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[N:21]=[C:20](/[CH:22]=[CH:23]/[CH2:24][NH2:25])[CH:19]=[CH:18][CH:17]=2)\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CN=[N+]=[N-])n2)cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CN)n2)cc1
Yield: 54 %

Procedure:
A solution of {3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enyl}-azide (154 mg, 0.43 mmol) in methanol (10 ml) was treated with tin (II) chloride (163 mg, 0.86 mmol). The reaction showed a slight exotherm and darkened in colour. After 1 hour solvent was removed under reduced pressure to leave a green gum. The residue was treated with sodium hydroxide solution (5M) and the product extracted (×4) with diethyl ether. The combined organic extracts were combined, dried over magnesium sulphate, filtered and solvent removed to yield {3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enyl}-amine as a brown gum (77.5 mg, 54%). 1H-NMR; δ (CDCl3), 7.43 (1H, t, J=8.1 Hz), 7.21 (3H, m), 7.09 (3H, m), 6.99 (1H, dt, J=16.3, 6.3 Hz), 6.69 (1H, d, J=8.0 Hz), 6.61 (1H, dt, J=15.6, 1.4 Hz), 3.56 (2H, dd, J=5.8, 1.3 Hz), 3.21 (2H, d, J=9.6 Hz), 2.56 (4H, m), 2.40 (3H, s), 1.79 (4H, s) and 1.71 (2H, bs).
Reaction SMILES: O[C@H:2]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+].[Br:42][C:43]1[CH:44]=[C:45]([CH:51]=[CH:52][C:53]=1[SH:54])[C:46]([O:48][CH2:49][CH3:50])=[O:47].N1C=CC=CC=1>C(#N)C.C(N(CC)CC)C>[Br:42][C:43]1[CH:44]=[C:45]([CH:51]=[CH:52][C:53]=1[S:54][C@H:2]([C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:46]([O:48][CH2:49][CH3:50])=[O:47]
Reactant: CCOC(=O)c1ccc(S)c(Br)c1
Reactant: COc1ccc(CCC[C@@H](O)C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)OCc2ccc([N+](=O)[O-])cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
The 4-nitrobenzyl (2R)-2-hydroxy-5-(4-methoxyphenyl)pentanoate (5.43 g) described in Reference Example 5 was dissolved in acetonitrile (20 ml), followed by adding thereto trifluoroacetic anhydride (5.1 ml) and then triethylamine (4.2 ml) at −30 to −20° C., and the resulting mixture was allowed to warm to room temperature spontaneously. After 30 minutes, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure and the residue was dissolved in acetonitrile (20 ml). The compound described in Reference Example 6 (ethyl 3-bromo-4-mercaptobenzoate (4.14 g, 15.7 mmol)) and then pyridine (1.28 ml, 15.7 mmol) were added thereto under ice-cooling. After 15 minutes, the resulting mixture was warmed up to room temperature. After 1 hour, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain ethyl 3-bromo-4-[((1S)-4-(4-methoxyphenyl)-1-{[(4-nitrobenzyl)oxy]carbonyl}-butyl)thio]benzoate (6.89 g) having an optical purity of 99% e.e. The optical purity analysis conditions are as follows. [Optical purity analysis conditions: column=OJ-R (Chiralcel, DAICEL Chemical Industries Ltd.); detecting wavelength (UV)=254 nm; flow rate: 1.0 ml/min; mobile phase=acetonitrile/water (68/32)]
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)C1=Cc2cc(C#N)ccc2OCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (1416 mg, 5.00 mmol), zinc cyanide (352 mg, 3.00 mmol), tetrakis(triphenylphosphine)palladium (347 mg, 0.30 mmol) and DMF(10 ml) was stirred at 80° C. for 3 hours. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. Insoluble materials were filtered off, which were washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate to give methyl 7-cyano-2,3-dihydro-1-benzoxepine-4-carboxylate (800 mg, 3.49 mmol, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21]2)=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:24][CH2:25]2)=[O:19])[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](CC(=O)O)Cc2ccc(Cl)cc2)CC1

Procedure:
A solution of tert-butyl (3S)-3-[(4-chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoate (Step 5) (0.16 g, 0.27 mmol) in 10 mL of 50% TFA in CH2Cl2 mixture was stirred at RT for 2 h. The volatile solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo. (3S)-3-[(4-Chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoic acid was obtained as a light yellow solid (0.14 g) MS (ESI, pos. ion) m/z: 534.4 (M+1). Calc'd for C26H32ClN3O5S: 533.18. Anal. Calcd for C26H32ClN3O5S 1.5H2O: C, 55.66; H, 6.29; N, 7.49; Cl, 6.32. Found: C, 55.51; H, 5.85; N, 7.35; Cl, 6.12.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][N:25]([CH3:24])[C:26]4=[O:30])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CN1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3)CC2)c(C)c1
Yield: 24.5 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 165 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (58 mg) was obtained.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:13]([CH:20](Br)[C:21]([OH:23])=[O:22])[CH2:14][CH:15](Br)[C:16]([OH:18])=[O:17].[OH-].[Li+]>O>[N:1]1([CH:15]([CH2:14][CH2:13][CH:20]([N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:21]([OH:23])=[O:22])[C:16]([OH:18])=[O:17])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNCCNCCN1
Reactant: O=C(O)C(Br)CCC(Br)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(CCC(C(=O)O)N1CCNCCNCCNCC1)N1CCNCCNCCNCC1
Temperature: 60 °C
Yield: 51.4 %

Procedure:
A mixture of cyclen (60.75 g, 350 mmol), meso-2,5-dibromoadipic acid (10.57 g, 35 mmol), and 1M lithium hydroxide (70 mL, 70 mmol) in water (104 mL) was heated to 60° C. under nitrogen for 170 hours. After cooling to ambient temperature, the reaction mixture was applied to an AG1X8 anion exchange column [400 mL (OH-form)]. The column was washed thoroughly with water (4 L), and the product was eluted with 0.5M acetic acid (2 L). Fractions containing product were combined, chased with water (3×200 mL) and ethanol (3×100 mL) to yield the title product (8.75 g, 51.8%) as a white, hygroscopic foam. Unreacted cyclen was reclaimed by concentration of the first 2 L of eluent and recrystallization from water. 1H NMR: (D2O) δ 2.75-2.90 (br mult, 34H), 1.52 (br, 4H). 13C NMR: (D2O) 24.3, 40.5, 41.1, 41.3, 41.6, 43.1, 44.9, 63.0, 177.1. MS (FAB): m/e 487.4 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.Br[CH:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:24]([S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)[CH2:23][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: BrC(Cc1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(SC(Cc3ccccc3)c3ccccc3)nc1-2
Yield: 41 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 1-bromo-1,2-diphenylethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 41%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.CO.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:13]
Reactant: Clc1ccc(Cl)nn1
Reactant: CNC
Solvent: CO
Product: CN(C)c1ccc(Cl)nn1
Yield: 96.3 %

Procedure:
3-(N,N-Dimethylamino)-6-chloropyridazine (108f, 510 mg, 96%) was prepared in the same manner as in Example 29 as a white solid using 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) and a 2.0 M dimethylamine methanol solution (NHMe2 in MeOH, 5 mL, 10 mmol).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[Si:6]([O:13][NH2:14])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(Cl)Cl>[Si:6]([O:13][N:14]=[CH:1][CH:2]=[CH:3][CH3:4])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C/C=C/C=O
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: ClCCl
Product: CC=CC=NO[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
The procedure followed was that described by Behforouz et al., J. Org. Chem. 58:7089-7091 (1993). In a 50 mL round bottom flask dry, 4 Å molecular sieves (Fisher, 3.4 g) were added to dry CH2Cl2 (distilled from CaH2, 10 mL) and cooled to 5° C. with an ice bath. Freshly distilled crotonaldehyde (Matheson Coleman & Bell, 0.725 mL, 0.618 g, 8.84 mmol) was added. A solution of O-(tert-butyldimethylsilyl)hydroxylamine (Aldrich, used without purification, 1.0 g, 6.80 mmol) in dry CH2Cl2 (distilled from CaH2, 3 mL) was added dropwise over a period of 5 min. The ice bath was removed and the mixture was stirred at rt under N2 for 18 h. The sieves were removed by filtration and the CH2Cl2 was evaporated to dryness (roto-vap). Column chromatography on silica gel with CHCl3 as eluent afforded 1-(tert-butyldimethylsilyloxy)-1-aza-1,3-pentadiene as a colorless light oil (1.2 g, 88%, interpretation of the 1H NMR showed a 1:1 anti/syn mixture): 1H NMR (CDCl3) δ (anti) 0.18 (s, 6H), 0.95 (s, 9H), 1.85-1.88 (m, 3H), 5.93-6.23 (m, 1H), 6.7-6.9 (m, 1H), 7.18 (d, 1H); (syn) 0.18 (s, 6H), 0.95 (s, 9H), 1.85-1.88 (m, 3H), 5.93-6.15 (m, 2H), 7.81 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([O:17][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][C:13]=1[CH:14]=[O:15])([CH3:26])[CH3:25])[CH3:24]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Yield: 88.8 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (2.28 g, 10.0 mmol), ethyl bromoisobutyrate (2.2 mL, 15 mmol), and cesium carbonate (3.26 g, 10.0 mmol) in dry DMF (25 mL) are heated at 80° C. for 18 h. The reaction mixture is cooled and partitioned between water (30 mL) and ether (75 mL). The organic layer is washed with brine (15 mL). The aqueous layers are back-extracted with ethyl acetate (30 mL), and the organic layer is washed with brine (20 mL). The combined organic layers are dried (Na2SO4) and concentrated to a brown oil. The crude product is purified by flash chromatography using hexanes:ethyl acetate (2.5:1) to give a pale yellow solid (3.04 g, 89%): mp 65° C.; 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d, 1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES) m/e 343.1 [M+1].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:10]=1)(=[O:3])[CH3:2].[Br:18]Br>C(=S)=S>[C:12]([O:11][C:9]1[CH:8]=[C:7]([C:15](=[O:17])[CH2:16][Br:18])[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:10]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(C)=O)c1
Reactant: BrBr
Solvent: S=C=S
Product: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)CBr)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4 g of 3',5'-diacetyloxyacetophenone was suspended in 75 ml of carbon disulfide. Thereto was dropwise added a solution of 0.90 ml of bromine dissolved in 25 ml of carbon disulfide, at room temperature in about 1 hour. The system was heated to about 50° C. occasionally in the course of dropwise addition and, each time when a reaction started, the system was returned to room temperature and stirred. After the completion of the dropwise addition, stirring was conducted at room temperature for 1 hour. After the completion of the reaction, the solvent was removed by distillation to obtain 5.53 g of 3',5'-diacetyloxy-2-bromoacetophenone as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1)=[O:6].C([O:24][P:25]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[C:37]([CH3:39])[C:36]([CH:40]=O)=[C:35]([CH3:42])[CH:34]=1)(=[O:29])[O:26]CC)C>>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:18]=[CH:19][C:20]3[N:21]=[C:40]([C:36]4[C:35]([CH3:42])=[CH:34][C:33]([CH2:32][CH2:31][CH2:30][P:25](=[O:24])([OH:29])[OH:26])=[CH:38][C:37]=4[CH3:39])[NH:1][C:2]=3[CH:3]=2)=[O:6])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(N)c(N)c2)cc1
Reactant: CCOP(=O)(C/C=C/c1cc(C)c(C=O)c(C)c1)OCC
Product: Cc1cc(CCCP(=O)(O)O)cc(C)c1-c1nc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1

Procedure:
The title compound was prepared from 3,4-diamino-N-(4-tert-butylphenyl)-benzamide (from Example 6-26) and [(E)-3-(4-formyl-3,5-dimethylphenyl)-allyl]-phosphonic acid diethyl ester analogous to Example 6-32. 1H NMR (Methanol-d4, 400 MHz): δ 8.25 (dd, 1H), 7.92 (dd, 1H), 7.72 (dd, 1H), 7.63 (m, 2H), 7.42 (m, 2H), 7.06 (s, 2H), 2.73 (t, 2H), 2.14 (s, 6H), 1.95 (m, 2H), 1.69 (m, 2H), 1.33 (s, 9H). MS (m/z) 520.2 (M+1); Retention time: 1.19 min (Method 10).