Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:15]([O:14][C:12]([NH:11][C:5]1([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][N:8]([S:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[Cl:19])(=[O:28])=[O:27])[CH2:7][CH2:6]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A mixture of 2 g (7.8 mmol) 4-tert-Butoxycarbonylamino-piperidine-4-carboxylic acid methyl ester, 1.72 g (8.1 mmol) 2-chlorobenzenesulfonyl chloride and 2.36 g (23 mmol) NEt3 in 30 mL DCM was stirred at room temperature over night. DCM and NaHCO3 aq. was added and the organic phase was dried with MgSO4 and evaporated. The ester (MS (m/e): 433.3 [(M+H)+]) was used without further purification. 3 g of the crude product was dissolved in methanol and 2.7 mL KOH aq. (5M), 30 mL water and 10 mL THF was added and the mixture was stirred at 55° C. for 5 h. The organic solvents were removed under vacuum and acetic acid was added. The mixture was extracted with ethyl acetate and the combined organic phases were washed with water, dried with MgSO4 and evaporated to yield 2.87 g of the title compound as white foam. MS (m/e): 419.1 [(M+H)+]
Reaction SMILES: NCCCCCC(O)=O.S(Cl)([Cl:12])=O.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26].Cl.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)CC)C>ClCCl.C(O)C>[ClH:12].[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[N+:25]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:15]=1[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:23][CH:22]=[CH:21][CH:20]=2)([O-:27])=[O:26]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: CCOC(=O)CCCCCN
Agent: Cl
Agent: NCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCCCCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Ethyl 6-aminocaproate hydrochloride was prepared from 6-aminocaproic acid, thionyl chloride, and ethanol by the general method of C. Temple, Jr., R. D. Elliott, and J. A. Montgomery, J. Med. Chem., 1988, 31, 697-700. The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (41.7 g, 200 mmol), ethyl 6-aminocaproate hydrochloride (46.9 g, 240 mmol) and triethylamine (50.6 g, 500 mmol) in dichloromethane for 15 hours to provide ethyl 6-(3-nitroquinolin-4-ylamino)hexanoate (60.6 g) as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].BrCCCCCC(C)C(OC)=[O:21].[O:25]1CCC[CH2:27][CH:26]1[O:31][CH:32]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:33][CH2:34][CH2:35][N:36]([CH2:40][CH2:41][CH2:42]CCC(C)C(OC)=O)C(=O)C>>[C:26]([O:31][CH:32]([CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:33][CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:40](=[O:21])[CH:41]=[CH2:42])(=[O:25])[CH3:27]
Reactant: COC(=O)C(C)CCCCCBr
Reactant: CCCCCC(CCCN(CCCCCC(C)C(=O)OC)C(C)=O)OC1CCCCO1
Reactant: CCOC(=O)CCCCCCBr
Product: C=CC(=O)N(CCCCCCC(=O)OCC)CCCC(CCCCC)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Exanple 1 except that, in Step A, the ethyl 7-bromoheptanoate is replaced by an equimolar amount of methyl 7-bromo-2-methylheptanoate (Example L, Step 4). The product of Step A is methyl 7-{N-[4-(2-tetrahydropyranyloxy)nonyl]acetamido}-2-methylheptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)acetamido]-2-methylheptanoic acid (B).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:58][C:59]1[CH:60]=[C:61]([N:65]2[C:69]([CH2:70][NH2:71])=[CH:68][C:67]([C:72]([F:75])([F:74])[F:73])=[N:66]2)[CH:62]=[CH:63][CH:64]=1>C1COCC1>[Cl:58][C:59]1[CH:60]=[C:61]([N:65]2[C:69]([CH2:70][NH:71][C:13](=[O:15])[CH:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=3)[CH3:16])=[CH:68][C:67]([C:72]([F:73])([F:74])[F:75])=[N:66]2)[CH:62]=[CH:63][CH:64]=1
Reactant: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(F)c1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.6 %

Procedure:
To a solution of 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoic acid (60 mg, 0.244 mmol) in THF (1.9 mL) was added 1-hydroxybenzotriazole (32 mg, 0.244 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (78 mg, 0.244 mmol), N-ethyldiisopropylamine (0.083 mL, 0.488 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (67 mg, 0.244 mmol). The solution was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate/cyclohexane (2:1)) to give pure N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3-fluoro-4-methylsulfonyl-phenyl)-propionamide (example compound D2) (93 mg, 76%).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH3:4].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[C:16]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:3](=[O:5])[CH3:4])=[CH:7]1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a stirred slurry of sodium hydride (3.77 g, 50% in oil, 7.86 mmol, extracted with hexanes) in THF (30 ml) at 0° C. under nitrogen was added dropwise 3-acetyl indole (10.0 g, 62.9 mmol) in THF (15 ml). After warming to room temperature and stirring one hour, the mixture was cooled to 0° C. and benzyl chloroformate (8.97 ml, 62.9 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. The excess sodium hydride was destroyed at 0° C. with 40 ml H2O. The mixture was then extracted three times with CHCl3 (total volume 120 ml), dried with MgSO4, filtered and evaporated to an off-white solid. Recrystallization from hexanes afforded 15.85 g (86%) of product: mp 112°-113°; Anal. Calcd for C18H15NO3 : C, 73.79; H, 5.16; N, 4.78. Found: C, 73.86; H, 5.29; N, 4.95.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[CH:13]2Cl)=[CH:4][CH:3]=1.O1CCOCC1.[NH3:26]>>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[CH:13]2[NH2:26])=[CH:4][CH:3]=1
Reactant: N
Reactant: COc1cc(F)c2c(c1)C(Cl)c1cc(Br)ccc1O2
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)C(N)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 60 h

Procedure:
7-Bromo-9-chloro-4-fluoro-2-methoxy-9H-xanthene (45 g, 131 mmol) was dissolved in saturated solution ammonia in dioxane (1310 mL, 655 mmol) and stirred for 60 hrs at RT. The solution was concentrated in vacuo. The material was treated with saturated aqueous sodium carbonate and extracted into EtOAc. The organic extracts were concentrated. The product was purified from the concentrate via silica gel column chromatography (RediSep 330 g column) using 10-100% EtOAc in hexane to afford 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-amine (10 g, 30:9 mmol).
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][C:16](Br)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:21](=[O:24])([O-])[O-].[Na+].[Na+].[CH2:27]1[CH2:31]O[CH2:29][CH2:28]1>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][N:11]1[C@H:12]2[C@@:27]([CH3:31])([C:27]3[CH:31]=[CH:10][C:4]([C:16]4[CH:15]=[C:14]5[C:19](=[CH:18][CH:17]=4)[N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[CH:12]=[CH:13]5)=[CH:5][C:28]=3[CH2:29][CH2:13]2)[CH2:28][CH2:29][C:21]1=[O:24]
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)ccc32)cc1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(-c4ccc5c(c4)CC[C@H]4N(C)C(=O)CC[C@]54C)ccc32)cc1
Yield: 15 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), N-tosyl-5-bromoindole (228 mg, 0.65 mmol), 0.65 mL of sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 49 mg (15%) of the title compound as an amorphous foam. FDMS: m/e=498.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:6]1)(=[O:4])=[O:3].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(=S)=S.C(Cl)Cl.O>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reaction time: 2 h

Procedure:
To a solution of 1-methylsulfonyl-3-(3-chlorophenyl)indoline (4.40 g, 14.3 mmol, see Preparation 5) and 4-chlorobenzoyl chloride (3.25 g, 18.6 mmol) in CS2 (25 mL) was added portionwise AlCl3 (7.62 g, 57.2 mmol) at about 0° C. A brown precipitate formed immediately. The mixture was stirred for about 2 hours. To the mixture was added slowly 100 mL of cold water containing 3 mL of concentrated HCl. The solution was diluted with DCM and the organic layer was separated and washed with 1N HCl aqueous solution (2 times), saturated NaHCO3 aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:2. The title compound was obtained as a solid. Yield=3.90 g, 61%. Rf=0.24 (silica, EtOAc/hexane 1:2). MS (ES): 445.2; Calc. MW=445.4, 1H NMR (300 MHz, CDCl3) δ: 7.67-7.76 (m, 3H), 7.53-7.59 (m, 2H), 7.48 (s, 1H), 7.44 (s, 1H), 7.30-7.32 (m, 2H), 7.20 (m1H), 7.09-7.14 (m, 1H), 4.65 (t, 1H), 4.50 (t, 1H), 3.98 (dd, 1H), 3.02 (s, 3H).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:13])[CH2:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].Cl>C(OCCOCCOCC)C>[C:6]1([OH:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:6]1([CH:7]=[CH:8][CH:9]=[C:10]([OH:12])[CH:11]=1)[OH:13]
Reactant: COC(=O)CCCC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCCOCCOCC
Product: Oc1cccc(O)c1
Product: Oc1ccccc1

Procedure:
A 1 liter four-necked flask, provided with mechanical stirrer, dropping funnel, thermometer and reflux condenser was charged with a mixture of 30 grams of sodium methylate and 400 grams of diethylene glycol diethyl ether. During the course of 1 hour at 25° C 48 grams of 5-oxohexanoic acid methyl ester were uniformly added. When the ester addition was terminated, gas chromatographic analysis indicated that the ester had completely reacted. Next, the reaction mixture was acidified to pH 3.5 by adding 46 ml of concentrated hydrochloric acid and the formed crystalline sodium chloride was filtered off with suction. Gas chromatographic analysis of the filtrate indicated a yield of cyclohexanedione-1,3 of 35.0 grams ≈ 94 %. 75 g of the filtrate which, according to gas chromatographic analysis, contained 6 grams of cyclohexane-dione-1,3 were added, over a period of 1 hour, to a dehydrogenation mixture heated to 185° - 190° C and consisting of 50 ml diethylene glycol diethyl ether and 1 gram of catalyst (0.1 gram palladium on 0.9 gram of carbon). As soon as the development of gas was terminated (1210 ml), the reaction mixture was cooled while flushing with nitrogen, the catalyst was filtered off with suction, washed with a little diethylene glycol diethyl ether, the filtrate was analyzed by gas chromatography and then distilled under reduced pressure. After a solvent fraction (boiling point under 15 mm Hg 78- 84° C) and a small amount of phenol, pure resorcinol was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.C([BH3-])#N.[Na+]>FC(F)(F)C(O)=O.CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C@@H:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C@@H:5]3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1ccc2c(c1)[C@H]1CN3CCC(CC3)[C@H]1N2
Temperature: 25 °C

Procedure:
A solution of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (1.2 g, 5.3 mmol; Example 2B) in trifluoroacetic acid (20 mL) was cooled to −30° C. A solution of sodium cyanoborohydride (1.75 g, 26.5 mmol; Aldrich) in methanol (6.5 mL) was added dropwise over a period of 30 minutes. The reaction mixture was allowed to slowly warm to ambient temperature over a period of 30 minutes, then diluted with methanol (60 mL) and concentrated under vacuum. The residue was purified by preparative HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 1.54-1.75 (m, 1H), 1.89-2.04 (m, 2H), 2.20 (s, 3H), 2.41-2.58 (m, 1H), 2.89-2.99 (m, 2H), 2.99-3.13 (m, 2H), 3.21-3.41 (m, 3H), 3.54-3.63 (m, 1H), 4.12 (dd, J=8.7, 5.0 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.83 (s, 1H); MS (+DCI) m/z 229 (M+H)+.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][CH:13]([CH:15]([OH:21])[C:16]([CH2:19][OH:20])([CH3:18])[CH3:17])[CH3:14]>C1(C)C=CC=CC=1>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:20])=[O:5].[CH3:17][C:16]([CH3:18])([CH:15]([OH:21])[CH:13]([CH3:14])[CH3:12])[CH2:19][OH:20]
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC(C)C(O)C(C)(C)CO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1C(=O)O
Temperature: 80 °C
Yield: 103 %

Procedure:
A solution of 4.98 g (0.033 mole) of phthalic anhydride and 5.42 g (0.037 mole) of TMPD in 40 mL of toluene was stirred and heated at 80° C. for approximately 30 hr. The solvent was evaporated and the crystalline residue washed with cold toluene and dried to give 5.95 g of 2,2,4-Trimethyl-1,3-pentanediol monophthalate. Crude 2,2,4-Trimethyl-1,3-pentanediol monophthalate (1.00 g) was recrystallized from 5 mL of toluene and washed to give 0.95 g of pure 1-(2,2,4-Trimethyl-1,3-pentanediol) monophthalate, m. p. (differential scanning calorimetry) 127.0° C.
Reaction SMILES: [OH-:1].[K+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]=2[O:4]1.[CH2:15](O)CO>>[OH:1][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1[O:11][CH:3]([OH:4])[CH3:15]
Reactant: [OH-]
Reactant: OCCO
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Agent: [K+]
Product: CC(O)Oc1ccc([N+](=O)[O-])cc1O
Temperature: -5 °C

Procedure:
0.2 mol (11.2 g) of potassium hydroxide is dissolved in 167 ml of ethylene glycol in a boiling water bath. 0.1 mol (16.7 g) of 3,4-methylenedioxynitrobenzene is added, with stirring, the temperature being kept in the region of 100° C. After heating for two hours, the reaction medium is cooled to -5° C. The expected product crystallizes in the form of the potassium phenate. The phenate is filtered off and then redissolved in 250 ml of water, and the solution is acidified to pH=6 with concentrated hydrochloric acid. The 2-hydroxy-4-nitrophenoxyethanol precipitates. After filtration, washing with water and drying in vacuo, the expected product melts at 158° C.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH:6][NH2:7])=[NH:5].C(O)C.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[ClH:11].[NH2:2][NH:3][C:4]([NH:6][N:7]=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)=[NH:5]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: N=C(NN)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(NN)NN=Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
The preparation of the subject compound may also be accomplished as follows: 25 g. of 1,3-diaminoguanidine hydrochloride is dissolved in 1800 ml. of boiling ethanol. To this boiling solution, 28 g. of 4-chlorobenzaldehyde in 300 ml. of ethanol is added over a period of 8 hours. The reaction mixture is then cooled at 0°C. overnight, clarified, and the filtrate concentrated to 500 ml. volume and cooled at 0°C. 29 g. of precipitate is obtained. This is slurried in 300 ml. of water, the pH adjusted to 8-8.5 with sodium hydroxide solution, the slurry heated to boiling and filtered. Cooling and filtrate gives 18 g. of essentially pure product melting at 243°-244°C., as in the previous preparation.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH2:15]([O:17][C:18](=[O:38])[C:19]([C:35](=[O:37])[CH3:36])=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH3:16].[NH4+].[Cl-]>C1COCC1.O>[CH2:15]([O:17][C:18](=[O:38])[CH:19]([C:35](=[O:37])[CH3:36])[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:22]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)C(=Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O
Reactant: Br[Mg]Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(C)=O)C(Cc1ccccc1)c1ccc(OC)c(OC2CCCC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Cuprous iodide (1.15 g, 6.05 mmol) in dry THF (10 ml) was treated at 0° C. with benzylmagnesium bromide (2M in THF, 6.05 ml, 12.1 mmol) over a 3 minute period. The cuprate was stirred at 0° C. for 30 minutes and then cooled to -78° C. and then TMSCl (3.28 g, 30.2 mmol) in THF (5 ml) was added dropwise keeping the reaction temperature below -60° C. The mixture was stirred at below -60° C. for a further 10 minutes and then ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-prop-2-enoate (1 g, 3.01 mmol) in THF (5 ml) was added dropwise over 3 minutes. The mixture was stirred at below -60° C. for 45 minutes and then saturated NH4Cl (30 ml) and water (20 ml) were added. The mixture was allowed to warm to room temperature, the resultant precipitate was removed by filtration and the filtrate evaporated, the residue was dissolved in methylene chloride (200 ml), washed with water (30 ml), In HCl (50 ml) and water (30 ml), dried over Na2SO, and the volatiles removed in vacuo. Flash chromatography (SiO2 ; EtOAc:hexane (1.9)) afforded ethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-4-phenyl-butanoate (1.19 g), 92%) as a yellow oil.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH2:8]=[CH:9][C:10](=[CH2:12])[CH3:11]>C1(C=CC=C(O)C=1O)O>[CH3:11][C:10]1[CH2:12][CH:3]2[CH:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)[CH2:8][CH:9]=1
Reactant: C1=CC2CCC1C2
Reactant: C=CC(=C)C
Agent: Oc1cccc(O)c1O
Product: CC1=CCC2C3CCC(C3)C2C1
Yield: 37.9 %

Procedure:
A mixture of 715 g (7.6 M) of norbornene, 550 g (8.1 M) of isoprene and 2 g of pyrogallol was heated in a stainless steel autoclave at ca. 150° during 15 hours. An internal pressure of 20 atm. is thus reached. The reaction mixture was then distilled by means of a Vigreux column and yielded 467 g (yield 38 %) of 5-methyl-tricyclo[6.2.1.02,7 ] undec-4-ene having b.p. 90°/10 Torr.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[C:17](=[O:33])[N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
3,4-Dimethylphenyl isocyanate (0.4 g, 3.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.8 g, 2.3 mmol) and triethylamine (0.3 g, 3.2 mmol) in THF (40 mL) at 5° C. After stirring for 10 minutes at 5° C., the mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL) for 30 minutes. The solid was collected and slurried with acetone (20 mL) to give 1-(3,4-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 82%) as a white solid: mp 222-224° C.; 1H NMR (DMSO-d6) δ 2.05-2.08 (m, 1H), 2.12 (s, 3H), 2.14 (s, 3H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.70 (d, J=5.8 Hz, 2H), 5.13-5.20 (dd, J=5.3 and 12.6 Hz, 1H), 6.69 (t, J=5.9 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.17 (s, 1H), 7.75-7.88 (m, 3H), 8.57 (s, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 18.60, 19.61, 21.99, 30.94, 38.72, 48.86, 115.33, 119.13, 121.84, 127.18, 128.75, 129.51, 131.60, 133.68, 134.71, 136.11, 137.96, 140.40, 155.29, 167.03, 167.61, 169.84, 172.78; Anal. calcd. for C23H22N4O5: C, 63.59; H, 5.10; N, 12.90. Found: C, 63.21; H, 5.09; N, 12.74.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:52])[CH:25]([C:27]1[CH:32]=[CH:31][C:30](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:29][CH:28]=1)[CH3:26].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:52])[CH:25]([C:27]1[CH:28]=[CH:29][C:30]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:31][CH:32]=1)[CH3:26]
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, 0.30 mmol), methyl-2-(4-iodophenyl)propionate (Reagent 1, 0.087 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.115 g, 86%).