Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.[CH3:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([CH2:27][N:28]2[C:32]([NH2:33])=[CH:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][N:28]2[C:32]([NH:33][CH:1]=[C:15]3[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]3=[O:19])=[CH:31][CH:30]=[N:29]2)=[CH:34][CH:35]=1.[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(Cn2nccc2N)cc1
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Cn2nccc2NC=C2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 80 °C

Procedure:
A stirred mixture of triethoxymethane (339 mL, 2037 mmol), and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) (35.2 g, 244 mmol) was heated to 80° C. for 1 hour. A suspension of 1-(4-methoxybenzyl)-1H-pyrazol-5-amine [41.4 g, 204 mmol; prepared according to the procedure described by Misra, R. N., et al. Bioorg. Med. Chem. Lett. 2003, 13, 1133-1136, except desalting was performed as follows: 1-(4-methoxybenzyl)-1H-pyrazol-5-amine hydrochloride (44 g) was partitioned between MTBE (300 mL) and 1N aqueous NaOH (300 mL), after separating the phases, the aqueous suspension was re-extracted with MTBE (8×100 mL), followed by drying (Na2SO4) the combined organic phases, and concentration in vacuo to obtain the free-based 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (30 g)] in triethoxymethane (339 mL, 2037 mmol) was added at once and heating at 80° C. was continued for 18 hours under N2. After cooling to room temperature, toluene azeotrope (2×200 mL) was utilized to remove EtOH. The resulting suspension was diluted with diethyl ether (500 mL) and filtered to obtain a yellow solid (33.5 g, 46%). 1H NMR (400 MHz, CDCl3) δ 11.13 (d, J=13 Hz, 1H), 8.26 (d, J=13 Hz, 1H), 7.50 (d, J=2 Hz, 1H), 7.25 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H), 6.21 (d, J=2 Hz, 1H), 5.28 (s, 2H), 3.78 (s, 3H), 1.74 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:32])[C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH2:25]([O:24][C:23]1[C:16]([CH3:15])=[CH:17][C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:21][C:22]=1[CH3:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(C=O)cc(C)c1OCc1ccccc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCc4ccccc4)c(C)c3)nc2c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
A mixture of 2-amino-4,6-dimethoxy-benzamide (0.71 g, 3.71 mmol), 3,5-dimethyl-4-benzyloxy benzaldehyde (0.94 g, 3.90 mmol), sodium hydrogensulfite (0.68 g, 3.90 mmol) and p-toluenesulfonic acid (70 mg, 0.37 mmol) in N,N-dimethylacetamide (25 mL) was stirred at 150° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). The resulting solid was collected by filtration and washed with hexanes to afford 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one as a white solid (1.2 g, 79%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=2[C:29](O)=[O:30])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>O1CCCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:28]=2[CH2:29][OH:30])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(CO)c1
Yield: 77.4 %

Procedure:
To a stirred suspension of 10 g of lithium aluminum hydride in 1 in liter dry ether under nitrogen was added over a period of one hour a solution of 35 g of 2-(4-benzyloxyphenylamino)-5-methoxybenzoic acid in 300 ml of tetrahydrofuran. The mixture was heated at reflux for three hours, then cooled, and water (20 ml) was slowly added. The solid material was removed by filtration and the filtrate concentrated in vacuo. The residue was crystallized and recrystallized from a benzene-cyclohexane-hexane mixture to yield 26 g of 2-(4-benzyloxyphenylamino)-5-methoxybenzenemethanol, light tan crystals, m.p. 100°-101° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.C(O)(=O)C>C1COCC1>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 158A (6.31 g, 21.7 mmol) and 30% aqueous acetic acid (100 mL) in THF (50 mL) was stirred at 95° C. for 6 hours, cooled to room temperature, concentrated, treated with water, and extracted with dichloromethane. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 248 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.N([O-])=[O:21].[Na+].[S:24]([Cl:27])(Cl)=[O:25]>C(O)(=O)C>[CH2:9]([O:8][C:7]1[CH:6]=[CH:5][C:4]([C:16](=[O:18])[CH3:17])=[CH:3][C:2]=1[S:24]([Cl:27])(=[O:25])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: O=S(Cl)Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1ccc(OCc2ccccc2)c(S(=O)(=O)Cl)c1
Reaction time: 0.47 h

Procedure:
1-(3-amino-4-benzyloxyphenyl)ethanone {2.41 g, prepared by the method reported by A. A. Larsen et al in J. Med. Chem., 10, 462-472 (1967)} was dissolved in acetic acid (5 ml) and thereto were added 5 ml of concentrated hydrochloric acid. Thereto was added an aqueopus solution (7 ml) of sodium nitrite (1.0 g) with agitation at −10° C. over a period of 50 minutes. The resulting mixture was agitated for further 28 minutes with ice-cooling, whereupon a solution of thionyl chloride (3.5 ml) in acetic acid (6.5 ml) and an aqueous solution (3 ml) of cupric chloride dihydrate (720 mg) were added thereto succeedingly, followed by agitation for 6 hours while getting the temperature thereof back to room temperature. The deposited precipitate was collected by filtration and dissolved in chloroform and the resulting solution was washed with water and dried, before it was concentrated to a volume of 50 ml under a reduced pressure to prepare a chloroform solution of 2-benzyloxy-5-acetyl-benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:48]=[C:49]=[O:50])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[C:31]([NH:48][C:49](=[O:50])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCCCCCCCCCC(=O)N=C=O
Agent: NC(=O)[O-]
Product: CCCCCCCCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 50 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with palmitoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 95 (207 mg, 50%) as oil. Rf 0.40 (EtOAc). PMR (CDCl3): δH0.88 (3 H, t like, CH3),1.25 (24 H, bs, --CH2 --), 1.31 (6 H, d, J 7.0 Hz, (CH3)2CH), 1.59 (2 H, m, --CH2 --), 2.59 (2 H, t, J 7.8 Hz, --CH2CO--, 3.19 (1 H, sep, J 7.0 Hz, (CH3)2CH), 5.22 (2 H, s, NCH2), 5.27 (2 H, s, OCH2), 6.70 (2 H, d, J 1.6 Hz, arom 2- and 6-H), 6.76 (2 H, d-like, 4-pyridyl 2- and 6-H), 7.06 (1 H, t, J 1.6 Hz, arom 4-H), 7.35 (1 H, bs, NH), 8.46 (2 H, d-like, 4-pyridyl 3- and 5-H). IR (CHCl3)cm-1 3394 (NH), 1792 and 1764 (NCO), 1716 (NCOO). Elementary analysis (for C34H46N4O3SCl2) Calcd.: C, 62.69% H, 7.31% N, 8.12% S, 4.65% Cl, 10.28% Found: C, 61.89% H, 7.66% N, 8.41% S, 4.56% Cl, 9.65% hydrochloride of the compound 95 mp. 158-160° C. Elementary analysis (for C36H52N4O3SCl4) Calcd.: C, 56.69% H, 6.87% N, 7.35% S, 4.20% Cl, 18.59% Found: C, 55.85% H, 6.71% N, 7.64% S, 4.28% Cl, 18.66%
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][N:12](CC2C=CC(OC)=CC=2OC)[CH2:11][N:10]([C:25]2[CH:26]=[N:27][N:28]([CH2:30][C:31]3[C:32]([CH3:37])=[N:33][O:34][C:35]=3[CH3:36])[CH:29]=2)[C:9]1=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.ClCCl>ClCCl>[CH2:1]([N:8]1[CH2:13][NH:12][CH2:11][N:10]([C:25]2[CH:26]=[N:27][N:28]([CH2:30][C:31]3[C:32]([CH3:37])=[N:33][O:34][C:35]=3[CH3:36])[CH:29]=2)[C:9]1=[O:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CN(Cc3ccccc3)C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2CNCN(Cc3ccccc3)C2=O)cn1
Yield: 57.6 %

Procedure:
1-benzyl-5-(2,4-dimethoxybenzyl)-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazinan-2-one (example 9-6a) (44 mg, 0.09 mmol), anisole (9 mg, 0.09 mmol), and 50% trifluoroacetic acid/dichloromethane solution (1 mL) in dichloromethane (1 mL) were stirred at room temperature for 2 hours. The reaction was concentrated, quenched with saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (2×, 50 mL) and washed with brine (50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by silica column chromatography (100% to 90% dichloromethane in methanol: 30 minute gradient) afforded 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazinan-2-one (19 mg, 62%) as a white solid. LC/MS; [M+H] calculated for C19H22N6O2; expected 367.18; found 367.20. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 5.84 μM.
Reaction SMILES: C[Si]([PH:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O-:9])[O:6][CH2:7][CH3:8])(C)C.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>O>[O:20]=[C:19]([CH3:21])[CH2:17][CH2:18][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: C=CC(C)=O
Reactant: CCOC(OCC)[PH]([O-])(OCC)[Si](C)(C)C
Solvent: O
Product: CCOC(OCC)P(=O)(CCC(C)=O)OCC
Reaction time: 0.5 h

Procedure:
A mixture of 2.7 g of ethyl trimethylsilyldiethoxymethylphosphonite and 0.7 g of methyl vinyl ketone is warmed to 50° for 1 hour under an atmosphere of nitrogen. Then 10 ml of water are added and the mixture is stirred for additional 30 minutes. The residue is extracted thrice with 50 ml of chloroform, the organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness. The residue is then distilled to yield ethyl 3-oxobutyl(diethoxymethyl)phosphinate, b.p. 130-5° (13.6 mbar).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5](O)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:34]1[C:39](O)=[CH:38][CH:37]=[C:36]([CH3:41])[CH:35]=1.N(C(OCC)=O)=NC(OCC)=O.[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([OH:59])=[O:58]>C1C=CC=CC=1.ClCCl.CCOCC>[C:54]([OH:61])(=[O:60])/[CH:55]=[CH:56]\[C:57]([OH:59])=[O:58].[CH3:1][N:2]1[CH2:7][CH2:6][C@@H:5]([C:39]2[CH:38]=[CH:37][C:36]([CH3:41])=[CH:35][CH:34]=2)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1
Reactant: Cc1ccc(O)cc1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)/C=C\C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccccc1
Product: Cc1ccc([C@@H]2CCN(C)C[C@H]2c2ccccc2)cc1
Temperature: 6 °C
Reaction time: 18 h

Procedure:
A mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol of Example 22, 7.21 g of triphenylphosphine, 2.97 g of p-cresol and 125 ml of anhydrous benzene is cooled to 6° C. and a solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added dropwise under nitrogen over a 90-minute period. The temperature is allowed to rise gradually so that at completion of the addition it is 22° C. After stirring for 18 hours at room temperature, the suspended solid is filtered off, washed with hexane, and the filtrate concentrated in vacuo to an oil. This material is triturated with 200 ml of hexane for 90 minutes, the liquid is decanted, and the solid triturated for a few minutes with another 200 ml of hexane. Concentration in vacuo of the hexane extracts affords an oil, which is dissolved in 250 ml of dichloromethane and extracted with 2 N HCl solution. The dichloromethane phase is washed successively with 10% aqueous NaOH solution, water, and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to a mixture of a solid and an oil. This mixture is triturated with hexane, filtered, and the filtrate is concentrated in vacuo to afford an oil. This oil is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent. The fractions containing product are combined and concentrated in vacuo to an oil which is taken up in ether and filtered through a Celite pad. The filtrate affords an oil which is triturated with boiling hexane and filtered hot. The filtrate is cooled and the resultant precipitated solid is filtered off and the filtrate concentrated in vacuo to yield an oil. This oil is dissolved in 50 ml of ether and added dropwise to a solution of 1.36 g of maleic acid in 25 ml of ether. The resulting solid is filtered, washed with ether, and dried to afford crude salt, melting near 100° C. Recrystallization from ethyl acetate affords a solid of trans-1-methyl-3-phenyl-4-(4-tolyl)piperidine maleate, mp s 130°, 131°-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:26][CH3:27])=[CH:14][C:3]=1[C:4](OCC1C=CC=CC=1)=[O:5].C(O)(=O)C.[CH:32](N)=[NH:33]>C(O)C(C)C>[CH2:19]([O:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4](=[O:5])[NH:33][CH:32]=[N:1]2)=[CH:14][C:15]=1[O:26][CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)c(N)cc1OCc1ccccc1
Reactant: N=CN
Solvent: CC(C)CO
Solvent: CC(=O)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Temperature: 97 °C
Reaction time: 6 h

Procedure:
Benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (5.55 kg), formamidine acetate (2.2 kg) and isobutanol (33.3 L) were mixed. The reaction mixture was then heated to 97° C. and stirred at this temperature for 6 hours. The reaction mixture was then cooled to 25° C. over a period of at least an hour and then stirred at this temperature for 30 minutes. The product (7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one) was isolated by filtration, washed with isobutanol (6.1 L) and dried in the vacuum oven at a temperature of from 40 to 45° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.Cl.O1CCOCC1>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][N:10]([CH3:12])[CH2:9][C:8](=[O:13])[NH:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CC(=O)Nc2cc(N)ccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C)C3)ncc1Cl
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 8-amino-4-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and 2-(2,5-dichloropyrimidin-4-ylamino)-N-methylbenzamide (22 mg, 0.08 mmol), and camphorsulfonic acid (17.4 mg, 0.08 mmol) were heated in IPA (3 mL) at 120° C. for 16 hours. The mixture was heated for another 2.5 hours at 120° C. after the addition of 10 drops of 4 N HCl/dioxane. Concentration and chromatography on preparative TLC with methylene chloride and methanol (100:8) followed by semi-preparative HPLC gave 5 mg of 2-[5-chloro-2-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (16% yield): 1H NMR (300 MHz, CD3OD) δ 8.7 (d, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.67 (m, 3H), 7.4 (m, 1H), 7.2 (m, 1H), 3.95 (s, 1H), 3.7 (s, 1H), 3.6 (s, 2H), 2.95 (s, 3H), 2.53 (s, 3H); MS (m/e): 452.2 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([Cl:35])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:20]=1)[C:11](OC)=[O:12]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([Cl:35])[C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:20]=1)[CH2:11][OH:12]
Reactant: COC(=O)c1cc(Cl)c(Oc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.4 %

Procedure:
To a stirred suspension of LiAlH4 (0.26 g, 6.95 mmol) in THF (40 mL) at 0° C. was slowly added a solution of methyl 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzoate (1.2 g, 2.76 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 h and cooled to 0° C. The reaction mixture was quenched with 15% aqueous NaOH (1.5 mL), diluted with H2O (3.0 mL) and stirred for 1 h. The reaction mixture was filtered through a Celite plug and the filtrate was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford 3,5-dichloro-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]benzyl alcohol as an oil (0.78 g, 70%): 1H NMR (300 MHz, CDCl3): δ 7.47 (s, 2 H), 7.16 (dd, J=6.0, 8.7 Hz, 2 H), 7.04 (t, J=8.7 Hz, 2 H), 6.84 (d, J=9.0 Hz, 1 H), 6.67 (d, J=3.0 Hz, 1 H), 6.45 (dd, J=5.4, 9.3 Hz, 1 H), 5.45 (t, J=5.7 Hz, 1 H), 4.48 (d, J=5.7 Hz, 2 H), 3.82 (s, 2 H), 3.69 (s, 3 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase ethyl acetate-hexanes (2:3); Rf=0.45.
Reaction SMILES: [CH:1]1=[CH:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10]1.[CH:11]1C=CC=C[CH:12]=1>[W](Cl)(Cl)(Cl)(Cl)(Cl)Cl>[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:12][CH:11]=1
Reactant: c1ccccc1
Reactant: C1=CCCCCC=CCC1
Agent: Cl[W](Cl)(Cl)(Cl)(Cl)Cl
Agent: C1=C\CCCC/C=C/CC/1
Product: C1=CCCCCCCCCCC1

Procedure:
Using the mode of operation set forth in Example 1--except for Experiment 31, wherein 15 ml. of monomer was employed--30 ml. (158 mmol.) of cyclododecene (mixture of isomers with 70.3% trans- and 29.7% cis-cyclododecene) was polymerized with a catalyst of varying amounts of cis,trans-1,5-cyclodecadiene and 1.5 ml. of a 0.1-molar solution of tungsten hexachloride in benzene. The results of Comparative Experiment B, as well as Experiments 31-38, are indicated in Table V.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH:15]=[C:16]1[NH:20][C:19](=[O:21])[CH2:18][S:17]1>>[NH:15]=[C:16]1[NH:20][C:19](=[O:21])[C:18](=[CH:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][N:4]=[C:3]3[NH:2][CH3:1])[S:17]1
Reactant: CNc1ncnc2ccc(C=O)cc12
Reactant: N=C1NC(=O)CS1
Product: CNc1ncnc2ccc(C=C3SC(=N)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([C:18]([C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][S:65][C:66](=[O:68])[CH3:67])[CH:59]=4)=[C:19]4[N:57]=[C:22]([C:23]([C:46]5[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][S:53][C:54](=[O:56])[CH3:55])[CH:47]=5)=[C:24]5[NH:45][C:27](=[C:28]([C:34]6[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:41][C:42](=[O:44])[CH3:43])[CH:35]=6)[C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].[Zn:69](OC(C)=O)OC(C)=O.O.O.O>C(Cl)(Cl)Cl.CO>[Zn+2:69].[C:66]([S:65][CH2:64][C:60]1[CH:59]=[C:58]([C:18]2[C:16]3[NH:17][C:13]([C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH:7]=4)=[C:32]4[N:33]=[C:29]([C:28]([C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:41][C:42](=[O:44])[CH3:43])[CH:35]=5)=[C:27]5[NH:45][C:24](=[C:23]([C:46]6[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][S:53][C:54](=[O:56])[CH3:55])[CH:47]=6)[C:22]6[CH:21]=[CH:20][C:19]=2[N:57]=6)[CH:25]=[CH:26]5)[CH:30]=[CH:31]4)=[CH:14][CH:15]=3)[CH:63]=[CH:62][CH:61]=1)(=[O:68])[CH3:67]
Reactant: CC(=O)O[Zn]OC(C)=O
Agent: CC(=O)SCc1cccc(-c2c3nc(c(-c4cccc(CSC(C)=O)c4)c4ccc([nH]4)c(-c4cccc(CSC(C)=O)c4)c4nc(c(-c5cccc(CSC(C)=O)c5)c5ccc2[nH]5)C=C4)C=C3)c1
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: [Zn+2]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 16.2 mg of 29 (16.7 μmol) in 20 mL of CHCl3 and a solution of 80.0 mg of Zn(OAc)2.2H2O (365 μmol) in 5 mL of methanol were combined and stirred at ambient temperature. After 2 h the metalation was completed (checked by fluorescence excitation spectroscopy) and 40 mL of H2O was added. The phases were separated and the organic layer was washed three times with 5% NaHCO3 and dried (Na2SO4). The solvents were removed under reduced pressure. Column chromatography over flash silica gel with CH2Cl2/hexanes (4:1) gave the title compound as a purple solid in quantitative yield. IR (neat): {tilde over (v)}=2922 (w, CH), 2849 (w, CH), 1690 (s, CO), 1655 (m, arom. C═C), 1600 (w, arom. C═C), 1478 (w), 1420 (w), 1338 (w), 1208 (m), 1131 (m), 1067 (w), 1002 (m), 955 (w), 932 (w), 794 (m), 717 (m); 1H NMR (300.5 MHz, CDCl3): δ=2.30 (s, 12H, CH3), 4.31 (s, 8H, CH2), 7.62–7.69 (m, 8H, ArH), 8.05–8.13 (m, 8H, ArH), 8.92 (s, 8H, β-pyrrole); LD-MS calcd av mass 1028.15 (C56H44N4O4S4Zn), obsd 1028.8, 986.6 [M+−COCH3], 954.7 [M+−SCOCH3], 911.3 [M+−SCOCH3—COCH3], 880.4 [M+−2 SCOCH3], 838.8 [M+−2 SCOCH3—COCH3], 805.3 [M+−3 SCOCH3]; λab's(toluene) 424, 550, 589 nm; λem (toluene) 597, 647 nm.