Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(P(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)=CC=1.C1(C)C=CC([S:29]([OH:32])(=[O:31])=[O:30])=CC=1.[H][H].[CH3:36][C@H:37]1[C:52]2[CH:53]=[CH:54][CH:55]=[C:56]([OH:57])[C:51]=2[C:50]([OH:58])=[C:49]2[C@@H:38]1[C@H:39]([OH:67])[C@@H:40]1[C@:46]([OH:59])([C:47]2=[O:48])[C:45]([OH:60])=[C:44]([C:61]([NH2:63])=[O:62])[C:42](=[O:43])[C@H:41]1[N:64]([CH3:66])[CH3:65].C[OH:69]>[Rh]>[CH3:36][C@H:37]1[C:52]2[CH:53]=[CH:54][CH:55]=[C:56]([OH:57])[C:51]=2[C:50]([OH:58])=[C:49]2[C@@H:38]1[C@H:39]([OH:67])[C@@H:40]1[C@:46]([OH:59])([C:47]2=[O:48])[C:45]([OH:60])=[C:44]([C:61]([NH2:63])=[O:62])[C:42](=[O:43])[C@H:41]1[N:64]([CH3:66])[CH3:65].[S:29]([C:53]1[CH:52]=[C:51]([C:50]([OH:58])=[O:69])[C:56]([OH:57])=[CH:55][CH:54]=1)([OH:32])(=[O:31])=[O:30]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: [H][H]
Agent: [Rh]
Agent: C[C@H]1c2cccc(O)c2C(O)=C2C(=O)[C@]3(O)C(O)=C(C(N)=O)C(=O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Agent: Clc1ccc(P(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Product: O=C(O)c1cc(S(=O)(=O)O)ccc1O
Temperature: 62 °C

Procedure:
A Parr bottle is charged with 5% rhodium-on-carbon (2.88 gms., 50% wet material; 0.70 mM of rhodium), tri-(4-chlorophenyl)phosphine (0.76 gms., 2.1 mM) in 13 cc. methanol. The mixture is shaken for a half-hour at 62°C., under nitrogen atmosphere, at the end of which time a solution of 3.39 gms., 7.0 mM, of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride in 37 cc. of methanol, containing 7.0 mM of p-toluenesulfonic acid, is added. The bottle is then filled with hydrogen at 50 p.s.i. and shaken overnight at 75°C. for 18 hours. High pressure liquid chromatography of the reaction mixture indicates the presence of 80% α-6-deoxy-5-hydroxytetracycline and 1.5% 6β-epimer. α-6-deoxy-5-hydroxytetracycline may be isolated in 78% yield as the 5-sulfosalicyclic acid salt.
Reaction SMILES: [CH3:1][N:2]([C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:12])[CH2:10]Br)[N:8]=1)[CH3:3].C(=O)([O-])O.[K+].Cl.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH2:32])[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]>CC(C)=O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([NH:32][CH2:10][CH:9]([OH:12])[C:7]2[N:8]=[C:4]([N:2]([CH3:3])[CH3:1])[S:5][CH:6]=2)[CH3:31])=[CH:25][CH:24]=1)([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: CN(C)c1nc(C(=O)CBr)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CC(C)NCC(O)c2csc(N(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g of 2-(N,N-dimethylamino)-4-bromoacetyl-thiazole in 250 ml of acetone are heated to reflux with 10 g of potassium hydrogen carbonate and 9.5 g of 2-(4-carbomethoxyphenyl)-1-methylethylamine-hydrochloride for 3 hours. After the reaction mixture has been cooled the inorganic products are removed by filtration, and the filtrate is concentrated in a rotary evaporator. The resulting oil residue is taken up in 150 ml of absolute methanol and, at 0°-5° C., 1.75 g of sodium borohydride are added in small poritons. The mixture is then stirred at 0°-5° C. for one hour and at room temperature for 24 hours. Then ice-water are added to the reaction mixture, and it is acidified with concentrated hydrochloric acid, made alkaline with ammonia, while cooling in ice, and extracted with methylene chloride. The extract is dried over sodium sulphate, concentrated and purified on a silica gel column using ethyl acetate/methanol=8:2 as eluant.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@@H:17]2[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C@H:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[C:10]([O:45][CH3:46])[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:31]1[CH:30]=[C:29]2[NH:28][C:27](=[O:36])[C@:19]3([C@@H:18]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[F:44])[C@H:17]([C:15]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:47])=[O:5])=[CH:9][C:10]=4[O:45][CH3:46])=[O:16])[NH:21][C@H:20]3[CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:34]2=[CH:33][CH:32]=1
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.8 %

Procedure:
A solution of chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-phenyl)-acetic acid tert-butyl ester (0.16 g, 0.23 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The “pH” of the residue was adjusted to 7 by aqueous saturated NaHCO3 solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with brine, dried over MgSO4, and concentrated, dried in vacuo to give chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-phenyl)-acetic acid as a light yellow solid (0.14 g, 95%).
Reaction SMILES: O.Cl.Cl.[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:8]=2[CH2:7]1.CN(C)C1CCC2[O:27][C:28]3[CH:33]=[CH:32][C:31](N)=[CH:30]C=3C=2C1.Cl.Cl.C1(C(Cl)=O)CCC1>>[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:28]([CH:33]4[CH2:32][CH2:31][CH2:30]4)=[O:27])=[CH:13][C:12]=3[C:8]=2[CH2:7]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Agent: Cl
Agent: O=C(Cl)C1CCC1
Solvent: O
Product: CN(C)C1CCc2oc3ccc(NC(=O)C4CCC4)cc3c2C1
Yield: 74 %

Procedure:
Beginning with 9.0 mg (0.029 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine dihydrochloride hemihydrate and 4.3 mg (0.036 mMol) of cyclobutanecarbonyl chloride, 6.7 mg (74%) of the title compound were recovered by the procedure described in Example 2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:31])[C:21]=1[CH3:32].CC(C)=[O:35]>S(=O)(=O)(O)O.O>[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[C:22](=[O:31])[C:21]=1[CH3:32])([OH:35])=[O:1]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCCO)=C(C)C1=O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCCCCCCCCC(=O)O)=C(C)C1=O

Procedure:
In 10 ml of acetone is dissolved 172 mg of 6-(18-hydroxyoctadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (V:n=17). Separately, 2.672 g of chromic anhydride is dissolved in 2.3 ml of concentrated sulfuric acid and diluted with water to 10 ml. This diluted solution (0.5 ml) is added to the above acetone solution and the mixture is stirred under ice-cooling for 10 minutes. The reaction mixture is diluted with water and extracted with chloroform. The extract is washed with water and dried, and the solvent is distilled off under reduced pressure. The residue is column-chromatographed on silica gel, elution is carried out with chloroform and the eluate is recrystallized from ethanol. The above procedure yields 65 mg of 6-(17-carboxyheptadecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (I:n=17, R=H) as orange-yellow crystals, m.p. 77°-79° C.
Reaction SMILES: C1(O)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.[N+](=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[O:21][CH2:20]1)=[N-]>>[CH2:31]([O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH:19]([O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=1)[C:28]2=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(O)c1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Solvent: Oc1ccccc1
Product: COc1cccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)c1

Procedure:
Replacing the phenol with a molar equivalent of 3-methoxyphenol, the method of Example 9 was employed to convert 3-diazo-6-benzyloxy-4-chromanone (76 g) to present title product, 5.5 g, m.p. 98°-100° C. 1H-NMR(CDCl3)delta(ppm): 3.85 (s, 3H), 4.45-4.65 (m, 2H), 5.0-5.2 (m, 3H), 6.5-7.6 (m, 12H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:35])([CH3:34])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([O:26]CC2C=CC=CC=2)[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3]>CO>[CH3:1][C:2]([Si:5]([CH3:35])([CH3:34])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:23]=[C:24]([OH:26])[CH:25]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1)=[O:15])[CH3:9])([CH3:3])[CH3:4]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CO
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (1.8 g, 3.64 mmol) was dissolved in methanol (50 mL) and the flask evacuated and purged with nitrogen (3 times). 10% Palladium on carbon (0.2 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off, and the filtrate concentrated in vacuo to give the desired compound (1.45 g). 1H NMR δ (d6-DMSO): 0.02 (d, 6H), 0.83 (s, 9H), 1.18 (d, 3H), 3.66 (m, 2H), 3.72 (s, 3H), 4.51 (m, 1H), 6.42 (m, 1H), 6.52 (m, 1H), 6.90 (s, 1H), 7.02 (s, 1H), 7.55 (m, 1H), 9.58 (br s, 1H), 10.59 (br s, 1H). m/z 406 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9]([CH:12]([CH3:14])[CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH:12]([N:9]1[CH2:10][CH2:11][C:6]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)([CH3:14])[CH3:13]
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(C(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(C)C)CC2)cc1

Procedure:
1-Isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4 -carboxylic acid was prepared starting from 1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (5.6 g, 15.2 mmol) dissolved in methanol (75 ml) and 10 N NaOH (25 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.18 g (42%); white powder; mp 204° C.; MS: 341.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[OH:13][N:12]=[C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)[NH2:2]
Reactant: NO
Reactant: N#Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=NO)c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 72.5 %

Procedure:
5-Cyano uracil (2.0 g, 14.6 mmol) was suspended in methanol (50 mL), then hydroxylamine hydrochloride (1.4 g, 20.0 mmol) and triethylamine (2.8 mL, 20.0 mmol) were added and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, the solid was collected by filtration, washed with methanol and dried to give the title compound as a pale yellow solid (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:36](Cl)(Cl)=[O:37].CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl.CO>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:36]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])=[O:37]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) and triethylamine (TEA, 120.0 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added phosgene solution (Aldrich, 20% in toluene, 0.40 mL, 0.4 mmol) by injection, and the reaction mixture was stirred at rt for 20 min. 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine* (65.2 mg, 0.45 mmol) was then added. The reaction mixture was stirred at rt for another 30 min then concentrated to give the crude product (checked by LCMS) which was diluted with MeOH and treated with PPTS (cat.) at 120° C. for 5 min with CEM microwave reactor. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 and washed with water and brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated under reduced pressure and purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide (62.5 mg, 39.5%, 2 steps) as a white amorphous. HRMS (ES+) m/z Calcd for C27H3Cl2F2N3O3+H [(M+H)+]: 554.1784; Found: 554.1787. *Preparation of intermediate 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25](=[O:30])[CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from [4-(4-chloro-phenoxy)-piperidin-1-yl]-oxo-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 198-200° C. (diethyl ether)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[I:8].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH3:9])[C:7]([I:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)cc(C)c1I
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(I)c(C)c1
Temperature: 25 °C

Procedure:
O-Methyl-3,5-dimethyl-4-iodophenol was prepared by etherifying 3,5-dimethyl-4-iodophenol as follows: In a 1 l three-necked flask equipped with an overhead stirrer were placed 63.7 g (257 mmol) of 3,5-dimethyl-4-iodophenol, 70.9 g (513 mmol) potassium carbonate, 400 ml acetone and 47.5 ml (108 g, 760 mmol) methyl iodide. The reaction mixture was refluxed for 15 hours, cooled, the precipitate filtered and washed with acetone. The combined acetone washes were concentrated under reduced pressure, dissolved in methylene chloride, washed successively with 5% sodium hydroxide, saturated sodium bisulfite and water. After drying over magnesium sulfate and filtering, the solvent was removed under reduced pressure to afford a tan oil. Recrystallization from hot methanol with cooling to room temperature and then -78° C. afforded 58.2 g (86% yield) of white needles, mp 33°-34° C., which were identified as O-methyl-3,5-dimethy-4-iodophenol. 1H NMR analysis indicated: (δ, CDCl3) 6.56 (s, 2H), 3.67 (s, 3H) and 2.37 (s, 6H). Mass spectrum analysis indicated: (m/e) 262 (m+, 100%), 247, 219, 135 and 91.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
To a solution of 1-hexylbenzene (5.00 g, 30.8 mmol) in CHCl3 (50 mL) was added chlorosulfonic acid (17 mL, 29.8 g, 256 mmol) and the mixture was stirred at rt for 20 h. The mixture was poured on ice (200 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, a solution of NaHCO3, and water, dried (Na2SO4), and concentrated in vacuo. The yellow oily residue (ca 81% yield) was used without further purification in the next reaction; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7 Hz), 1.30-1.35 (m, 6H), 1.55-1.63 (m, 2H), 2.59 (t, 2H, J=8 Hz), 7.38 (d, 2H, J=8 Hz), 7.89 (d, 2H, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)N([O])C(C)(C)CCC1.OS([O-])(=O)=O.[K+]>C(OC(C)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)C
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Temperature: 2.5 °C

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.0 eq.) in isopropyl acetate (5 vol) was cooled to 0° C. and TEMPO (0.05 eq.) was added. A solution of bleach (12.5 wt %, 1.2 eq., 2.6 vol) was then slowly added over 1 hour while maintaining the temperature at 0-5° C. The mixture was stirred and monitored by HPLC for completion, then aqueous 10% KHSO4 (2.5 vol) was added, stirred for 10 minutes, and then the phases were separated. The organic phase was washed with aqueous 5% Na2SO3 (2 vol) then brine (1 vol) then dried azeotropically and concentrated to afford the title compound as a solid. The solid was triturated with acetonitrile (1.0 vol) to remove residual color and impurities. 1H-NMR (400 MHz, DMSO): δ 4.54 (m, 1H), 3.82 (m, 1H), 3.67 (m, 1H); 3.15 (m, 1H); 2.50 (m, 1H, coincides with DMSO); 1.42 and 1.39 (2 s rotamers, 9H).
Reaction SMILES: [Li+].[OH-:2].C([O:5][C:6](=[O:23])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)C>C1COCC1.CO.O>[O:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:23])=[O:2])=[CH:11][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CNCc1ccc(Oc2ccccc2)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
LiOH (4.81 g, 114.63 mmol) was added to a stirred solution of (4-phenoxy-benzylamino)-acetic acid ethyl ester (5.72 g, 19.12 mmol) in THF:MeOH:H2O (3:1:1, 75 mL), and the resulting mixture was stirred at room temperature for 5 hrs. The MeOH and THF were evaporated, and the residue was acidified with cold 20% aqueous HCl. The resulting precipitate was filtered, washed with water and dried to afford 4.74 g (91.41% yield) of (4-phenoxy-benzoylamino)-acetic acid. 1H NMR (DMSO): δ 7.8 (d, 2H,), 7.75 (t, 1H), 7.4 (t, 2H), 7.15 (t, 1H), 7.05 (d, 2H), 7.0 (d, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.O=[Si]=O.[CH2:8]([O:10][C:11]([NH:13][NH2:14])=[O:12])[CH3:9]>O>[CH2:8]([O:10][C:11](=[O:12])[NH:13][N:14]=[CH:3][CH2:2][Cl:1])[CH3:9]
Reactant: O=CCCl
Reactant: CCOC(=O)NN
Agent: O=[Si]=O
Solvent: O
Product: CCOC(=O)NN=CCCl
Reaction time: 0.5 h

Procedure:
550 g (3.5 mol) of a 50% aqueous solution of chloroacetaldehyde were diluted with 3000 ml water and were reacted with 10 g Celite 545 in order to react with the precipitating resin. For this purpose the solution was passed through a fluted filter into a three times tubulated round bottom flask of 6 l contents which was provided with a stirrer and thermometer. While cooling with ice a solution of 364 g (3.5 mol) of hydrazinoformicacid ethylester in 360 ml water was added during a period of 15 min. The temperature within the reaction vessel was maintained at between 0° and 5° C. There formed immediately a thick white crystal slurry. Stirring was continued at room temperature for 30 minutes. The crystals were then removed by suction, were washed neutral with about 6 liters water and were dried in a vacuum at 30° C. until the weight remained constant.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3one (264 mg, 0.786 mmol), in 3.0 mL of 1,4-dioxane was added DDQ (196 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (911 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 55 mg (21%) of the title compound as an orange solid. mp 205°-206°. FDMS m/e=334. α[D]589 =+57.23 (c=0.66, chloroform).