Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(N[C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[C:27]([C:31]1[CH:40]=[C:39]2[C:34]([C:35](=[O:41])[CH2:36][CH2:37][O:38]2)=[CH:33][CH:32]=1)([O:29][CH3:30])=[O:28].C(#N)C>C(O)(C)C>[OH:41][C@@H:35]1[C:34]2[C:39](=[CH:40][C:31]([C:27]([O:29][CH3:30])=[O:28])=[CH:32][CH:33]=2)[O:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CC(C)O
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)OCC[C@@H]2O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of (1S,2S)-TsDPEN (1.709 g, 4.85 mmol) in isopropanol (5 mL) was added to a 35 mL schlenk-flask and cooled to 0° C. The solution was degassed by three cycles of evacuation/nitrogen refill. Then, [RuCl2(η6-p-cymene)]2 (1.313 g, 2.425 mmol) was added, followed by TEA (1.352 mL, 9.699 mmol). The reaction mixture was heated to 80° C. under N2 for 1 h and cooled. The iso-propanol was removed under a stream of nitrogen, and dissolved in 10 mL acetonitrile. The catalyst solution was added to nitrogen filled 1 L 3-N flask equipped with overhead stirring. 7-Carbomethoxy-4-chromanone (100 g, 485 mmol) and 400 mL acetonitrile was added to the flask, followed by 5:2 formic acid-TEA (50 mL). The reaction mixture was incubated for 24 h at 30° C. An additional portion of formic acid-TEA (5 mL) was added and the reaction mixture stirred for an additional 24 h. The solution was concentrated completely by rotary evaporation. The product was purified by crystallization from 200 mL 2-propanol and 100 mL hexanes. The solids were collected by filtration and washed with cold 2:1 iPrOH-Hex. Final drying of the solids afforded the title compound. MS (m/z): 208.9 (m+H). Chiral HPLC showed the enantiomeric purity to be greater than 98%, when compared to racemic material.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]([CH2:9][C:10]1[C:11]([Cl:16])=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:18][CH2:19][OH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cccnc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: OCCN(Cc1ccccc1)Cc1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of the compound (11.8 g) obtained in step 1 in THF (30 mL) was added 1M BH3-THF complex/THF solution (134 mL) at 0° C., and the mixture was stirred at 90° C. for 1 hr. After the reaction mixture was cooled to 10° C., MeOH (20 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in 6N hydrochloric acid (43 mL), and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled to 10° C., and made basic with aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give 2-{benzyl[(2-chloropyridin-3-yl)methyl]amino}ethanol (6.92 g, 86%) as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7](=[N:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[N+:2]=[N-:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>N1C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[N:15]=[C:16]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[CH3:24])[O:25]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1C(=O)NN=C(CCCN=[N+]=[N-])c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(Cl)cc1C1=NN(C(=O)C(C)(C)C)C(CCCN=[N+]=[N-])(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of N′-(4-azido-1-phenylbutylidene)-5-chloro-2-methyl benzohydrazide (100 mg, 0.28 mmol) in pyridine (1 mL) was added pivaloyl chloride (70 μL, 0.56 mmol). After stirring at room temperature for 16 hours the heterogeneous mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed successively with 10% NaHSO4 (2×10 mL), NaHCO3 (10 mL) and brine (10 mL) then dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (9:1 hexanes/EtOAc) to afford the product (62 mg, 50%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[CH3:29].[Li+].CC([N-]C(C)C)C>C1COCC1>[Si:1]([O:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10](=[O:12])[CH2:29][C:28]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CC(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.4 %

Procedure:
To a solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-3-methylbutanoic acid (1.0 g, 4.3 mmol) in THF (14.3 mL) at 0° C. were added carbonyldiimidazole (1.05 g, 6.45 mmol). After 15 min, the mixture was allowed to warm to ambient temperature and stirred for 48 h. This solution was cooled to −78° C. and added to a solution of preformed enolate by mixing benzyl acetate (2.18 mL, 15.1 mmol) and LDA (2.0 M in THF; 7.53 mL, 15.1 mmol) in THF (15 mL) at −78° C. The mixture was stirred at −78° C. for 1 h then warmed to −10° C. for 30 min. The mixture was cooled back to −78° C. and quenched with sat. NH4Cl. The mixture was extracted with dichloromehtane (3×). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→75% hexanes/ethyl acetate) gave the title compound (0.43 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:34][CH2:33][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=O)[O:19][C:20](=[O:31])[C:21]=4[C:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[O:24][CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].C[Si](C)(C)[NH:37][Si](C)(C)C.CO>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]1[CH2:34][CH2:33][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:19])[NH:37][C:20](=[O:31])[C:21]=4[C:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[O:24][CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CC(=O)OCC1CCn2c(c(C3=C(c4coc5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)OCC1CCn2c(c(C3=C(c4coc5ccccc45)C(=O)NC3=O)c3ccccc32)C1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of 1.0 g of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)furan-2,5-dione in 100 ml of chloroform was treated with 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol and the solution obtained was heated to 50° C. while stirring under a nitrogen atmosphere for 6 hours. An additional 13.8 ml of hexamethyldisilazane and 2.73 ml of methanol were added and the heating was continued for 16 hours. Two more additions of the same quantities of hexamethyldisilazane and methanol were effected and the temperature of the mixture was held at 50° C. for an additional 24 hours. Then, 20 ml of methanol were added and the mixture was heated to reflux for 15 minutes, cooled and concentrated. The precipitate was filtered off and triturated in succession with ethyl acetate and methanol. There were obtained 630 mg of 3-[8-(acetoxymethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(3-benzofuranyl)-1H-pyrrole-2,5-dione of melting point 234°-237° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([OH:18])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(O)C1=C(Sc2ccccc2)CC2CC(=O)C12
Yield: 84.1 %

Procedure:
A solution of 150 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, and 135 mg of anisole in 3 mL of trifluoroacetic acid was stirred at room temperature for 15 min. The solvent was removed with a stream of nitrogen leaving a residual oil which when triturated with ether afforded 77 mg (84%) of colorless crystals of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid. NMR (220 MHz; CDCl3): δ 2.27 (1H, dd, J=17, 3), 2.75 (1H, m), 2.68 (1H, m), 3.0-3.25 (1H, m), 4.50 (1H, m), 7.2-7.4 (3H, m), and 7.4-7.6 (2H, m).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:29])[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:25])[O:23][CH3:24])[C@H:18]1[C:26]([OH:28])=[O:27].[O:30]([C:37]1[S:38][C:39]([CH2:42]O)=[CH:40][N:41]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:29])[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:25])[O:23][CH3:24])[C@H:18]1[C:26]([O:28][CH2:42][C:39]1[S:38][C:37]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:41][CH:40]=1)=[O:27]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H]1[C@@H](C(=O)OCc2cnc(Oc3ccccc3)s2)C1(C)C
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
0.1 g of 4-dimethylamino-pyridine and then 0.97 g of dicyclohexylcarbodiimide were added to a solution of 1 g of (1R,3S) 2,2-dimethyl-3-[(E) 3-oxo-3-methoxy-propen-1-yl)-cyclopropane-1-carboxylicacid in 20 ml of methylene chloride and the mixture was stirred at 20° C. for 15 minutes. A solution of 1.24 g of (2-phenoxy-5-thiazolyl)-methanol in 15 ml of methylene chloride was added dropwise at 10° C. to the mixture. The mixture was stirred at 20° C. for 4 hours and was filtered. The filtrate was treated with activated carbon, was washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 8-2 hexane-ethyl acetate mixture yielded 1.09 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-[(E) 3-oxo-3-methoxy-propen-1-yl)-cyclopropane-1-carboxylate with a specific rotation of [α]D° =+60.5° (c=1.5% in benzene) and melting at 62° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromophenol (35.0 g, 145 mmol) in acetic acid (250 ml) was treated with N-iodosuccinimide (32.5 g, 145 mmol) at RT. The reaction mixture was stirred at RT for 18 h. The reaction mixture was filtered to remove the solid and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica) eluting with 1% methanol in chloroform to afford the title compound as a brown liquid.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Br:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[C:47](I)=[CH:46][C:45]=1[Cl:53].[NH2:54][C:55]1[CH:60]=[CH:59][C:58]([S:61][CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:57][C:56]=1/[C:69](/[CH3:76])=[CH:70]\[C:71]([O:73][CH2:74][CH3:75])=[O:72].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:62]([S:61][C:58]1[CH:59]=[CH:60][C:55]([NH:54][C:47]2[CH:46]=[C:45]([Cl:53])[C:44]([Br:43])=[CH:49][C:48]=2[O:50][CH3:51])=[C:56](/[C:69](/[CH3:76])=[CH:70]\[C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH:57]=1)[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: CCOC(=O)/C=C(/C)c1cc(SCc2ccccc2)ccc1N
Reactant: COc1cc(Br)c(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C(/C)c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(Br)cc1OC

Procedure:
A solution of xantphos (0.265 g, 0.458 mmol), pd2(dba)3 (0.140 g, 0.153 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (1.167 g, 3.36 mmol), (Z)-ethyl 3-(2-amino-5-(benzylthio)phenyl)but-2-enoate (1.000 g, 3.05 mmol), and potassium phosphate (1.945 g, 9.16 mmol) in 10 mL dioxane was heated to 100° C. for 2 hours. The reaction mixture was then poured into water and extracted with DCM. The organics were dried over MgSO4 and concentrated. The crude residue was used in the next step without purification. m/z (ESI) 546.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=C)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:19].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH2:1]([O:3][C:4]([CH:6]1[C:10]([CH3:11])=[C:9]2[C:12](=[C:16]=[O:19])[CH:13]=[CH:14][CH:15]=[C:8]2[O:7]1)=[O:5])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2oc(C(=O)OCC)c(C)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1Oc2cccc(=C=O)c2=C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
To a solution of 0.250 g (1.087 mmol) of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester (Example 87, Step 1) in 7.5 mL of dioxane and 2.5 mL of water was added 0.272 mL of 2.5 weight % osmium tetroxide in t-butanol (0.022 mmol) and the reaction was stirred for 10 minutes at room temperature, turning yellow-brown in color. Sodium periodate (0.488 g, 2.282 mmol) was then added in several portions over 30 minutes and a white precipitate formed. The reaction was stirred at room temperature for 2 h and then diluted with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.225 g of 4-carbonyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[O:8][N:7]=1)=O)C.[OH-].[NH4+:19]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([NH2:19])=[O:3])[CH:10]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)on1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cc(-c2ccc(Cl)cc2)on1
Reaction time: 72 h

Procedure:
Ethyl-5-(4-chlorophenyl)-3-isoxazolecarboxylate (139 grams) and 1.5 l. of conc. aqueous ammonium hydroxide were placed in a 2 l. 3-necked flask and stirred with a mechanical stirrer for 3 days. Following this, the reaction mixture was poured into 2 l. of water, filtered, and washed with water. The resulting dry solid was swirled with 1.6 l. of chloroform for 1/2 hour, filtered, and then dried in a vacuum oven for 3 hours, m.p. 224°-225° C.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10](=[O:22])[C:11]([C:19](=[O:21])[CH3:20])=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7])[CH3:4]>Br>[Br:1][CH2:20][C:19]([C:11]1[C:10](=[O:22])[NH:9][C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=1)=[O:21]
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Reactant: BrBr
Agent: Br
Product: CCOC(=O)c1cc(C(=O)CBr)c(=O)[nH]c1C(=O)OCC
Temperature: 0 °C

Procedure:
Bromine (8.0 g, 0.050 mol) in 48% HBr is added dropwise to a stirred solution of diethyl-5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate (14.05 g, 0.05 mol) in 48% HBr (200 mL). Upon completion of this bromine addition the reaction mixture is poured onto ice (200 g) and the mixture is stirred until the ice has melted. Th crude product is collected by filtration and crystallized twice from an ethyl acetate-hexane mixture (1/2) affording diethyl 5-(bromoacetyl)-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate with mp 141°-142° C.
Reaction SMILES: O1CC1COC1C=CC=CC=1C#N.N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1.[CH3:28][C:29]([N:41](CC(O)COC1C=CC=CC=1C#N)[CH2:42][CH:43]([OH:54])[CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]#[N:53])([CH3:40])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.[ClH:68]>CC(O)C.CO.CCO>[ClH:68].[OH:54][CH:43]([CH2:42][NH:41][C:29]([CH3:40])([CH3:28])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[CH2:44][O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]#[N:53]
Reactant: CC(C)(Cc1c[nH]c2ccccc12)N(CC(O)COc1ccccc1C#N)CC(O)COc1ccccc1C#N
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: N#Cc1ccccc1OCC1CO1
Solvent: CCO
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(Cc1c[nH]c2ccccc12)NCC(O)COc1ccccc1C#N
Reaction time: 18 h

Procedure:
A solution of 2-[(2,3-epoxy)propoxy]benzonitrile (18.3 g., 0.10 mole) and 2-(3-indolyl)-1,1-dimethylethylamine (15.2 g., 0.08 mole), in 500 ml. of abs. EtOH was stirred at reflux overnight. After concentration of the reaction mixture to approximately 200 ml. and seeding, crude product began to precipitate. The mixture was then cooled and the precipitate separated by filtration to give 24.8 g. of the free base form of the product, white solid, m.p. 120°-123°. The crude solid was dissolved in 400 ml. of boiling MeOH, and the solution was cooled with stirring, as a by-product 1,1'-[[1,1-dimethyl-2-(1H-indol-3yl)ethyl]imino]bis[3-(2-cyanophenoxy)-2-propanol] precipitated. The by-product was collected on a filter and air dried to give 2.2 g., m.p. 180°-187°. The MeOH filtrate was then taken to dryness. The residual solid was dissolved in 200 ml. of i-PrOH and acidified with ethanolic HCl. Seeding followed by 18 hours standing in the cold afforded the product as the crystalline hydrochloride. Filtration of the mixture gave 19.8 g., of solid, m.p. 179°-183°. One recrystallization from abs. EtOH gave 15.5 g. (48%) of white solid, m.p. 185°-187°. TLC on silica gel (9CH2Cl2, 10 MeOH, 1NH4OH) showed a single spot (Rf =0.5, u.v.).
Reaction SMILES: [C:1]12([NH:11][C:12]#[N:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:14].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[ClH:14].[C:1]12([NH:11][C:12]([NH:21][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[NH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NC1CCCCC1
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Agent: Cl
Product: N=C(NC1CCCCC1)NC12CC3CC(CC(C3)C1)C2
Temperature: 200 °C

Procedure:
Adamantan-1-yl-cyanamide (514 mg, 2.92 mmol), and cyclohexylamine hydrochloride (398 mg, 2.93 mmol) were finely ground together, and heated at 200° C. for 10 min. The resultant glassy solid was pulverized, and extracted twice with 50 ml boiling 5% HCl. The insoluble material was filtered, and dried. 346 mg, mp 264°-270° (p.h.b. 240° C.). On cooling the combined aqueous extracts to 25°, a white ppt. formed, and was filtered off, 56 mg. Combined crude yield: 44%. Crystallization of a 50 mg sample of the crude product from EtOH/Et2O afforded white needles (25 mg, mp 269°-271° C. (p.h.b. 240°), lit. 268°-269° C.). 1H (CD3OD) 1.208-1.474 (m, 5H), 1.744 (s, 9H), 1.967 (s, 8H), 2.119 (5, 3H), 3.434 (m, 1H), 13C (CD3OD) (broad band decoupled) 25.55, 26.26, 30.96, 33.74, 36.74, 42.73.
Reaction SMILES: [CH3:1][C:2](=[C:4]([CH3:6])[CH3:5])[CH3:3].[OH-].[Na+].ClS([N:13]=[C:14]=[O:15])(=O)=O>C1(C)C=CC=CC=1.O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:3])[C:4]([CH3:6])([CH3:5])[NH:13][C:14]1=[O:15]
Reactant: CC(C)=C(C)C
Reactant: O=C=NS(=O)(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)NC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,3-dimethyl-2-butene (5.76 g) in toluene (46.0 mL), chlorosulfonyl isocyanate (5.91 mL) was added at 0° C. After being stirred at that temperature for 10 minutes, the mixture was brought to room temperature. After being stirred for 45 minutes, the mixture was diluted with added toluene (69.0 mL). To a mixture of a solution of 25% sodium hydroxide in water (49.1 mL) and benzyltriethylammonium chloride (99.0 mg), the reaction mixture was added over a period of one hour. The resulting mixture was added dropwise to a solution of 25% sodium hydroxide in water and the mixture was stirred at 50° C. for an hour. After being cooled to room temperature, the mixture was extracted with toluene twice. The combined organic layers were washed with saturated brine and dried over added anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized with toluene to give 3,3,4,4-tetramethylazetidine-2-one as a colorless solid (5.52 g).
Reaction SMILES: [CH2:1]([C:3]1[C:20]([O:21][CH3:22])=[N:19][C:6]2[CH2:7][CH2:8][N:9](C(=O)C(F)(F)F)[CH2:10][CH:11]([CH3:12])[C:5]=2[CH:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].CO>O>[CH2:1]([C:3]1[C:20]([O:21][CH3:22])=[N:19][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH:11]([CH3:12])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCc1cc2c(nc1OC)CCNCC2C
Yield: 40.6 %

Procedure:
A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-3-vinyl-6,7,8,9-tetrahydro -5H-pyrido[2,3-d]azepine (52 mg, 166 μmol), 5% Pd/C (20 mg), and MeOH (20 ml) was stirred under H2 (1 atm) for 15 h. Filtration and concentration of the filtrate in vacuo yielded 36.0 mg (69%) of 3-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 317.3. A mixture of 3-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (36.0 mg, 114 μmol), K2CO3 (100 mg), MeOH (5 ml) and H2O (1 ml) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 10.2 mg (40%) of 3-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (MeOH-d4) δ 7.30 (s, 1H), 3.89 (s, 3H), 3.17 (m, 5H), 3.06 (m, 1H), 2.87 (m, 1H), 2.57 (m, 2H), 1.31 (d, 3H), 1.15 (t, 3H) ppm.