Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:4][C:5](=O)[CH2:6][CH2:7][CH2:8][C:9]1([CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]1=[O:24])C.B.CO>C1COCC1>[ClH:1].[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1([CH2:25][C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]1=[O:24]
Reactant: CCOC(=O)CCCC1(Cc2ccncc2)C(=O)N(c2ccccc2)c2ccccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C1N(c2ccccc2)c2ccccc2C1(CCCCO)Cc1ccncc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 2,3-Dihydro-2-oxo-1-phenyl-3-(4-pyridinylmethyl)-1H-indole-3-butanoic acid ethyl ester hydrochloride (10.0 g, 22.2 mmol) in 50 ml dry THF was treated with excess 1M BH3 -THF and stirred at room temperature for 3 days. The excess borane was decomposed with MeOH, and the mixture was concentrated in vacuo. The residue was digested with 100 ml 1N HCl for 3 hours at 80° C. , and the solution was concentrated. The residue was partitioned between 200 ml EtOAc and 100 ml 5% NaHCO3. The organic phase was washed with water and brine, dried over MgSO4, filtered, treated with 44 ml 1N HCl-Et2O, evaporated in vacuo. The residue was suspended in hot CH3CN and left standing overnight. The resulting crystals were collected by filtration, washed with Et2O, and dried to give the product in 30% (2.72 g) yield; mp 196°-197° C.; IR(nujol): OH @3356 cm-1 ; C=O @1709 cm -1 ; NMR(CDCl3TMS): δ1.13, 1.24 (2m, 2H, CH2 --C--CO), 2.51 (m, 2H, CH2 --CO), 2.1-3.0 (m, 2H, CH2 --C--C--CO), [3.40 (d, 1H, J=12.4 Hz), 3.54 (d, 1H, J=12.5 Hz), CH2 -Pyr], 3.48 (t, 2H, OCH2), [6.5 (m, 1H), 7.2 (m, 2H), 7.4 (m, 6H), Phe+1,2-Phe], [6.99 (d, 2H), 8.49 (d, 2H), 4-Pyr]; mass spec m/e 373(M+1); Anal calcd for C24H24N2O2HCl, MW 408.93: C, 70.49; H, 6.16; N, 6.85. Found: C, 70.44; H, 6.00; N, 6.67.
Reaction SMILES: CN([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)CCCCCCCCCCCO.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(O)(=O)C>O>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][N:33]=[CH:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:22][CH:21]=2)=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CN(CCCCCCCCCCCO)c1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(NN=Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 8.62 g of 4-[N-methyl-N-(11-hydroxyundecyl)-amino]-benzaldehyde, 4.33 g of 4-nitrophenylhydrazine and 25 ml of glacial acetic acid were [sic] refluxed for 30 minutes and left to stand overnight at room temperature. 70 ml of ice water were added to the resulting reaction mixture and the mixture was stirred thoroughly After the water had been removed from the reaction mixture, the reaction product, which had now precipitated, was separated off and then subjected to preliminary purification by boiling with active carbon in acetone. The prepurified product was then purified by flash chromatography on silica gel, a mixture of hexane and ethyl acetate in a volume ratio of 6:4 being used as the mobile phase. A total of 3.4 g of 4'-N-methyl-N-(11-hydroxyundecyl)-amino]-benzaldehyde-4-nitrophenylhydrazone were obtained, corresponding to a yield of 28% of theory. In its IR spectrum, this product, in the form of a KBr pellet, had bands at 3,400, 3,250, 1,585, 1,510, 1,490, 1,460, 1,320, 1,290, 1,270, 1,170, 1,100, 830 and 810 cm-1.
Reaction SMILES: Cl.C([O:9][C:10]([C:12]1([C:15](=[O:47])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]4[CH2:38][CH2:37][CH:36]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]5)[CH2:35][CH2:34]4)=[O:32])[CH:25]=3)=[CH:19][C:18]=2[F:46])[CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1.[OH-].[Na+]>O.C(OCC)(=O)C>[F:46][C:18]1[CH:19]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)[CH2:35][CH2:34]3)=[O:32])[CH:25]=2)[CH:21]=[CH:22][C:17]=1[NH:16][C:15]([C:12]1([C:10]([OH:11])=[O:9])[CH2:14][CH2:13]1)=[O:47]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester hydrochloride (2 g) was dissolved in water (20 ml) and ethyl acetate (20 ml), and a 2N aqueous solution of sodium hydroxide (4 ml) was added, and the layers were separated. The organic layer was washed with water and concentrated. Addition of tetrahydrofuran and subsequent concentration was repeated three times. The residue was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (1.6 ml), and palladium on carbon (200 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (0.2 MPa) for 5 hours. Tetrahydrofuran (4 ml) and methanol (6 ml) were added to the reaction mixture, which was filtered. The residue was washed with 90% aqueous methanol (3 ml). Tetrahydrofuran (12 ml) and the seed crystals obtained in (Method 1) were added to the filtrate, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (32 ml) was added, and the mixture was stirred for 14 hours. The crystals were filtered and dried to give the title compound (1.2 g) as white crystals.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=C[C:5]=1O)[CH2:2]C.[Br:11]Br.[C:13]([OH:16])(=O)[CH3:14]>>[Br:11][C:2]1[CH:1]=[C:4]([CH2:9][CH2:8][CH3:7])[CH:5]=[CH:14][C:13]=1[OH:16]
Reactant: CCCc1ccccc1O
Reactant: BrBr
Reactant: CC(=O)O
Product: CCCc1ccc(O)c(Br)c1
Temperature: 60 °C

Procedure:
Following step (4) of the reaction system, 20.5 g (0.15 mol) of a commercial grade n-propylphenol was dissolved in 100 ml of glacial acetic acid and heated to 40° C. with 24.5 g (0.153 mol) of bromine dissolved in 50 ml of glacial acetic acid. The mixture was stirred and heated at 60° C. for 4 hours. After the reaction was complete, the acetic acid was removed by distillation and the remaining liquid was distilled under reduced pressure to yield 2 mmHg of 2-bromo-4-n-propylphenol having a boiling point of 73° to 76° C. The 2-bromo-4-n-propylphenol was cyanized in accordance with step (5) as in Example 1 to yield 2 mmHg of 2-cyano-4-n-propylphenol (hereinafter referred to as material G) having a boiling point of 110° C. Materials F and G are esterified in accordance with step (6) as in Example 1 to yield the desired (2'-cyano-4'-propyl) phenol-3-chloro-4-n-heptyloxybenzoate. The benzoate had a melting point of 43.5° C. and an infrared absorption spectrum as illustrated in FIG. 10.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C-:13]#[N:14].[Na+]>[Cu]I.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>[O:12]=[C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:13]#[N:14])[CH:3]=2)[NH:8]1
Reactant: [C-]#N
Reactant: O=C1CCc2cc(I)ccc2N1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: N#Cc1ccc2c(c1)CCC(=O)N2

Procedure:
6-Iodo-3,4-dihydroquinolin-2(1H)-one (1.50 g; 5.50 mmol), sodium cyanide (0.54 g; 11.0 mmol), copper (I) iodide (0.105 g; 0.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g; 0.3 mmol) were combined in a flask equipped with a reflux condenser. The flask was subjected to several evacuation-nitrogen purge cycles followed by the addition of acetonitrile (25 mL). The reaction was heated to reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate (200 mL), filtered through CELITE diatomaceous earth and rinsed with copious amounts of ethyl acetate. The organic solution was washed twice with brine (50 mL), dried over sodium sulfate, filtered through a fritted funnel, and the volatiles were removed under vacuum. The crude residue was crystallized from methanol, which afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[B:15](OC)([O:18]C)[O:16]C.Cl>CCCCCC.O1CCCC1>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([B:15]([OH:18])[OH:16])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1c(Cl)cccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cccc(Cl)c1F
Temperature: -80 °C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
In a 500-mL three-neck flask was put 16 g (72 mmol) of 1-bromo-3-chloro-2-fluorobenzene, and the air in the flask was replaced with nitrogen; then, 200 mL of tetrahydrofuran was added and the solution was cooled down to −80° C. under a nitrogen stream. To this solution, 48 mL (76 mmol) of n-butyl lithium (a 1.6 mol/L hexane solution) was added dropwise with a syringe, and then the mixture was stirred for 1.5 hours at the same temperature. After stirring, 9.0 mL (80 mmol) of trimethyl borate was added to this mixture. While the temperature was raised to room temperature, the mixture was stirred for about 19 hours. After stirring, about 100 mL of a 1 mol/L hydrochloric acid was added to the resulting solution and the mixture was stirred. The organic layer of this mixture was washed with water and the aqueous layer was subjected to extraction with toluene twice. The solution of the extract and the organic layer were combined and washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over magnesium sulfate, and this mixture was gravity-filtered. The resulting filtrate was concentrated to give 4.5 g of a pale yellow solid of a target substance, in a yield of 35%.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:26]#[N:27])[C:8]([CH3:25])=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]=2[N:11]2[CH2:15][CH2:14][C@H:13]([N:16]([CH3:18])[CH3:17])[CH2:12]2)[N:6]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37].[OH-].[Na+]>ClCCl.O>[C:26]([C:7]1[C:5]2[N:6]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[O:3][C:4]=2[C:10]([N:11]2[CH2:15][CH2:14][C@H:13]([N:16]([CH3:17])[CH3:18])[CH2:12]2)=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]=1[CH3:25])#[N:27]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N)nc2c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NS(C)(=O)=O)nc2c1C#N

Procedure:
2-Amino-7-[3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (#76) was suspended in dichloromethane (3.4 ml), then triethylamine (94.9 μl, 681 μmol) and methanesulfonyl chloride (52.7 μl, 681 μmol) were added with cooling with ice, then dichloromethane (10 ml) was added, followed by stirring with cooling with ice for 5 hours. Further, triethylamine (94.9 μl, 681 μmol) and methanesulfonyl chloride (52.7 μl, 681 μmol) were added with cooling with ice, followed by stirring at room temperature for 15 hours. Aqueous 1 N sodium hydroxide solution (5 ml) and water (5 ml) were added to the reaction liquid, and the aqueous layer was washed with diethyl ether (20 ml×2).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[CH:8]=2)=[N:4][C:3]=1[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21]2.[Li+].[OH-].O>C(O)C.C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[CH:8]=2)=[N:4][C:3]=1[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21]2
Reactant: C=Cc1cccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)OCC)c(C)o2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C=Cc1cccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(C)o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.9 %

Procedure:
To a solution of ethyl ((1S)-5-{2-[5-methyl-2-(3-vinylphenyl)-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (40 mg, 0.09 mmol) in ethanol (1.0 mL) and THF (1.0 mL) was added LiOH (39 mg) followed by water (1 mL). The reaction mixture was then stirred at rt for 4 h. The reaction mixture was then acidified to pH 5-6 and concentrated under reduced pressure. The residue redissolved in methanol, and filtered through a C8-Silica plug. The filtrate was then purified by preparative HPLC using with 10 to 70% acetonitrile in water to afford 27.2 mg (72%) of desired product. 1H NMR (CD2Cl2) δ 7.97 (s, 1H), 7.79 (d, 1H), 7.42 (d, 1H), 7.35 (t, 1H), 7.02 (d, 1H), 6.62-6.76 (m, 3H), 5.80 (d, 1H), 5.27 (d, 1H), 4.14 (t, 2H), 3.43 (qr, 1H), 2.90 (t, 2H), 2.66-2.83 (m, 3H), 2.29-2.43 (m, 5H), 1.67-1.72 (m, 1H). EI-LCMS(rel abundance), RT=3.95, m/z 404.4 (MH+, 72%).
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.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1>>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][C:22]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: Cc1ccc(C)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(=O)c2ccccc2C(=O)O)c1

Procedure:
Monomers. The spirobislactone endcapping group, 4-carboxy-7,7'-dioxa-2,2'-spirobi (benzo[c]tetrahydrofuran) 5,was synthesized using a three-step procedure. Phthalic anhydride (PA) 1 was reacted with p-xylene 2 in the presence of AlCl3 to produce ##STR6## 2,5-dimethyl-2'-carboxybenzophenone 3. Oxidation by potassium permanganate yielded the triacid 4 which was cyclized to 5 by refluxing with Dowex 50X8-100 resin (H+) in 2-methoxyethyl ether and removing the water of reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([NH:18][C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH2:67]([OH:73])[CH:68]1[O:72][CH2:71][CH2:70][CH2:69]1>O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:3]=[C:2]([O:73][CH2:67][CH:68]3[CH2:69][CH2:70][CH2:71][O:72]3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: OCC1CCCO1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(OCC2CCCO2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 200 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 246 mg of tripotassium phosphate, 111 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 60 mg of tris(dibenzylideneacetone) (chloroform)dipalladium, 4 ml of tetrahydrofurfurylalcohol and 2 ml of 1,4-dioxane were added, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 1 hour. The reaction solution was diluted with ethyl acetate and was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 77 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]([O-])=[O:20].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[N:19][OH:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nccc(CC(=O)c2cccc(Br)c2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nccc(C(=NO)C(=O)c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12.75 g (39.5 mmol) C1 were dissolved in a mixture of 173 ml glacial acid, 136 ml tetrahydrofurane and 17 ml water. After cooling to 5° C. a solution of 3.24 g (47.0 mmol) sodium nitrite in 25 ml water was added keeping the temperature between 5° C. and 10° C. The cooling was removed and the mixture stirred for 6 hours at room temperature. After removal of the solvent in vacuo 320 ml water and 320 ml ethyl acetate were added. The pH was adjusted to 8 with 3 N NaOH. The phases were separated and the aqueous layer was extracted with 50 ml ethyl acetate. The combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo. The residue was treated with diethylether, filtered off and dried. Yield: 8.33 g (60%) D1, m.p. 156–158° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[C:22]1(=[O:31])[N:1]([CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: CC(C)CC(N)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a stirred solution of d,l-leucine (3.31 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carboethoxyphthalimide (5.65 g, 25.0 mmol). After 1 hour at room temperature, the reaction slurry is filtered, the filtrate stirred, and the pH adjusted to 1-2 with 4N hydrochloric acid. The mixture is stirred overnight, the resulting slurry is filtered, and the solid washed with water and dried in vacuo (60° C., <1 mm) to afford 5.32 g (81%) of the 2-phthalimido-4-methylpentanoic acid as a white powder: mp 134°-137° C.; 1H NMR (DMSO-6, 250M Hz) δ12.50 (br s, 1H), 8.00-7.80 (m, 4H), 4.79 (dd, 1H, J=4.3), 2.28-2.10 (m, 1H), 1.94-1.77 (m, 1H), 0.89 (d, 3H, J=4.4), 0.86 (d, 3H, J=4.5); 13C NMR (DMSO-d6) δ170.8, 167.4, 134.8, 131.1, 123.3, 50.2, 36.7, 24.6, 23.0, 20.8. Anal. Calculated for C14H15NO4. Theoretical: C, 64.36; H, 5.74; N, 5.36. Found: C, 64.18; H, 5.73; N, 5.98.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[OH:20])([CH3:10])[CH3:9].[C:21](Cl)(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27].[OH2:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:21]([OH:29])(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:20][C:12]1[C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]([CH3:19])[CH3:18])=[O:27]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1OC(=O)CCCCC(=O)O
Reaction time: 2 h
Yield: 40 %

Procedure:
Triethylamine (6.26 ml, 45 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol) in methylene chloride (30 ml) were added to a solution of 2,6-diisopropylphenol (5.2 ml, 28 mmol) and adipoyl chloride (4.4 ml, 30 mmol) in methylene chloride (50) at 0° C. The mixture was allowed to reach room temperature and stirred at that temperature for 2 hr. Water (50 ml) was added, and the two-phase mixture was stirred for 1 hr. The organic phase was washed with 3% aqueous HCl and then dried. Solvents were removed under vacuum, and the oily residue was chromatogrammed on a silica gel column using chloroform-methanol (10:0.1) and then chloroform-methanol-acetic acid (10:0.1:0.01). The fractions containing the ester were pooled and evaporated under vacuum to yield 3.4 g (40% yield) of 2,6-diisopropylphenol hydrogen adipate (propofol hemiadipate) as an oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:11].[NH2:12][C:13]1[N:17]2[C:18]3[C:37](Br)=[CH:36][C:35](CC)=[CH:34][C:19]=3[C:20]([C:24]3[CH:29]=[CH:28][C:27](C(F)(F)F)=[CH:26][CH:25]=3)=[N:21][CH:22](C)[CH:16]2[N:15]([CH2:41]CC)[NH+:14]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[OH-:8].[C:1]1([S:7]([NH:12][C:13]2[N:17]3[C:18]4[CH:37]=[CH:36][C:35]([Cl:11])=[CH:34][C:19]=4[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21][CH2:22][CH:16]3[N:15]([CH3:41])[NH+:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN1[NH+]=C(N)N2c3c(Br)cc(CC)cc3C(c3ccc(C(F)(F)F)cc3)=NC(C)C12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: [Cl-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1[NH+]=C(NS(=O)(=O)c2ccccc2)N2c3ccc(Cl)cc3C(c3ccccc3)=NCC12
Product: [OH-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To an ice cold stirred solution of 0.388 g. (0.0022 mole) of benzenesulfonyl chloride in 15 ml. of dried pyridine, 0.721 g. (0.002 mole) of 1-amino-8-chloro-3-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinium chloride (VI) is added. The resulting mixture is kept in an ice bath for about 15 hours and then allowed to warm to room temperature and stand for about 6 hours. It is then poured into cold, dilute aqueous sodium bicarbonate solution and extracted with chloroform. The extract is washed with brine, dried with sodium sulfate and concentrated. The residue is crystallized to give 1-benzenesulfonamido-8-chloro-3-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinium hydroxide inner salt (X).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1OCC)#[N:2].[CH3:16]C1C=C([N+]([O-])=O)C=CC=1C#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:10])=[O:11])=[CH:5][C:4]=1[CH3:16])#[N:2]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: Cc1cc([N+](=O)[O-])ccc1C#N
Product: Cc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 2-methyl-4-nitro-benzonitrile.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][CH:13]3[C:8]=2[CH2:9][CH2:10][NH:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH:29](Br)([CH3:31])[CH3:30]>CN(C)C=O>[CH:29]([N:11]1[CH2:10][CH2:9][C:8]2[CH:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1)([CH3:31])[CH3:30]
Reactant: CC(C)Br
Reactant: c1ccc(C2=C3CCNCC3Cc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC2=C(c3ccccc3)c3ccccc3CC2C1
Reaction time: 3.5 h

Procedure:
A mixture of 22.0 g of 1,2,3,4,10,10a-hexahydro-5phenylbenz[g]isoquinoline, 20.0 g of sodium carbonate and 0.2 g of sodium iodide in 180 ml of dimethylformamide are preheated to 50°. 16.5 g of isopropylbromide in 50 ml of dimethylformamide are added dropwise to the suspension over a 2 hour period, the reaction mixture further stirred for 3.5 hours at the same temperature, cooled and poured onto ice/water. The organic substance is extracted with benzene, the extracts washed with water, dried over sodium sulphate and evaporated and the title compound which remains converted to the fumarate form in isopropyl. M.P. 199°-200°.