Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([OH:17])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:15]([NH:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])=[O:29])=[O:17]
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
A solution of N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (0.23 g), benzenesulphonamide (129 mg), dimethylaminopyridine (0.22 g) and 1-ethyl-3-(3-dimethylaniinopropyl)carbodiimide hydrochloride (0.19 g) in dichloromethane was allowed to stir for 24 hours at room temperature. 2N HCl was added and the reaction stirred vigorously for 2 hours, then extracted with dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated to yield the desired end product as a white crystalline solid (122 mg, 32%); NMR δ (CD3SOCD3) 5.65 (s, 2H), 6.73 (dd, 1H), 7.12 (m, 2H), 7.30 (t, 1H), 7.38 (d, 1H), 7.56 (m, 4H), 7.70 (m, 2H), 7.91 (d, 2H); M/z (−) 457 (M−H+).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C>[Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: Brc1csc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1sc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
Into a solution of 3-bromobenzo[b]thiophene (40 g, 190 mmol) in glacial acetic acid (140 ml) was added a solution of nitric acid (74 ml, 1760 mmol) in glacial acetic acid (40 mL) over a period of 45 min. The reaction mixture was stirred at room temperature for 5 hours before quenching with water. The precipitate was isolated by filtration, washed with water and recrystallized from ethyl acetate/hexane (1/1, v/v) to yield 3-bromo-2-nitrobenzo[b]thiophene (35 g, 72%) as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](OCC)=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[B-](CC)(CC)CC>C1COCC1.C(=O)=O.C(#N)C>[OH:15][CH2:14][C:12]1[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[S:10][CH:11]=1
Reactant: CCOC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: CC[B-](CC)CC
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1nc(CO)cs1
Temperature: -45 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
Ethyl 2-(tert-butoxycarbonylamino)thiazole-4-carboxylate 88 (10.5 g, 38.6 mmol) was dissolved in 300 mL of anhydrous THF and cooled in dry ice-acetonitrile bath. A solution of 1 M Super Hydride™ in THF (85 mL) was then added over a period of 10 min. The resulting reaction mixture was stirred at −45° C. for 2 h. Another portion of 1 M Super Hydride™ in THF (35 mL) was then added and the reaction mixture was stirred for an additional 2 h at −45° C. The reaction was quenched at −45° C. by the addition of 50 mL of brine. Upon warming to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 89 (6.39 g, 72% yield).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[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][CH3:18].[NH3:21]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19].[NH3:21]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: N
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 80 °C

Procedure:
Separately, 100 ml of pure water was charged in a 200-ml capacity beaker and heated at 80° C., and 0.93 g of stearic acid was added to heated water under agitation by a glass rod to melt stearic acid. Then, 0.21 ml of aqueous ammonia having a concentration of 3.953 moles/l was added to the mixture under violent agitation to completely emulsify stearic acid and form an ammonia soap suspension having a pH value of 10.5.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]2[CH:32]=[C:31]([CH2:33][CH3:34])[S:30][C:24]=2[NH:25][C:26](=O)[CH2:27][N:28]=1>N1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]2[CH:32]=[C:31]([CH2:33][CH3:34])[S:30][C:24]=2[NH:25][C:26](=[S:2])[CH2:27][N:28]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1cc2c(s1)NC(=O)CN=C2c1ccccc1Cl
Solvent: c1ccncc1
Product: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 136 %

Procedure:
Diphosphorus pentasulphide (32 g) is added to a solution of 40 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e] [1,4]diazepin-2-one on 20 ml of pyridine, and the resulting mixture is stirred at 60° C for 1 hour, and then allowed to cool. Then, the reaction mixture is poured into 2 liters of ice water under cooling, and the precipitate is collected by suction filtration, washed well with water and dissolved in chloroform. The chloroform solution is washed with an aqueous sodium hydrogen carbonate solution and then with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue is recrystallized from a mixture of ethanol and chloroform to give 31.4 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e] [1,4] diazepine-2-thione as yellow crystals, melting at 198°-199° C with decomposition.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[C:9]([NH2:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[C:1]([NH:14][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=C(C)C(N)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.8 %

Procedure:
Into the same reaction vessel as used in Example 1, ethoxalyl chloride (12.3 g; 0.09 mol) was charged, and the reaction vessel was cooled in an ice bath. A solution of methacrylamide (7.7 g; 0.09 mol) in chloroform (32.4 ml) was dropwise added thereto in 10 minutes. After completion of the addition, a mixture of pyridine (7.2 g; 0.09 mol) and chloroform (10 ml) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was shaken with chloroform (500 ml) and water (500 ml), and the chloroform layer was separated and dried over anhydrous magnesium sulfate, followed by removal of chloroform. Hydroquinone (0.01 g) was added thereto, and distillation under reduced pressure was carried out to give N-ethoxalylmethacrylamide (5.3 g). Yield, 32%.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:31]([CH3:32])[C@@H:30]2[C@@:5]([C:34]([O:36][C@@H:37]3[O:42][C@H:41]([CH2:43][O:44][C@@H:45]4[O:50][C@H:49]([CH2:51][OH:52])[C@@H:48]([O:53][C@@H:54]5[O:59][C@@H:58]([CH3:60])[C@H:57]([OH:61])[C@@H:56]([OH:62])[C@H:55]5[OH:63])[C@H:47]([OH:64])[C@H:46]4[OH:65])[C@@H:40]([OH:66])[C@H:39]([OH:67])[C@H:38]3[OH:68])=[O:35])([CH2:6][CH2:7][C@:8]3([CH3:33])[C@:13]4([CH3:29])[CH2:14][C@@H:15](O)[C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1>C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OC[C@H]3O[C@@H](OC([C@]45CCC(C)(C)C[C@H]4C4=CC[C@@H]6[C@@]7(C)C[C@@H](O)[C@H](O)[C@](CO)(C)[C@@H]7[C@H](O)C[C@@]6(C)[C@]4(C)CC5)=O)C(O)[C@@H](O)C3O)O[C@@H]2CO)[C@H](O)[C@H](O)[C@H]1O>[CH3:1][C@H:2]1[C@H:31]([CH3:32])[C@@H:30]2[C@@:5]([C:34]([O:36][C@@H:37]3[O:42][C@H:41]([CH2:43][O:44][C@@H:45]4[O:50][C@H:49]([CH2:51][OH:52])[C@@H:48]([O:53][C@@H:54]5[O:59][C@H:58]([CH3:60])[C@H:57]([OH:61])[C@@H:56]([OH:62])[C@H:55]5[OH:63])[C@H:47]([OH:64])[C@H:46]4[OH:65])[C@@H:40]([OH:66])[C@H:39]([OH:67])[C@H:38]3[OH:68])=[O:35])([CH2:6][CH2:7][C@@:8]3([CH3:33])[C@:13]4([CH3:29])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5[C@H](O)C[C@]43C)[C@H]12
Agent: C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OC[C@H]3O[C@@H](OC(=O)[C@]45CCC(C)(C)C[C@H]4C4=CC[C@@H]6[C@@]7(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]7[C@H](O)C[C@@]6(C)[C@]4(C)CC5)C(O)[C@@H](O)C3O)O[C@@H]2CO)[C@H](O)[C@H](O)[C@H]1O
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12

Procedure:
The solution thus obtained is filtered and then concentrated, in a reactor under reduced pressure, until an aqueous phase is obtained, according to the same principle as the preceding concentration. It is then readjusted by adding ethanol in order to obtain a stabilized aqueous-alcoholic solution having a solids content of 200 g+/−20 per liter and an alcohol percentage of 35%+/−3.5% volume/volume. A prepurified phase rich in madecassoside and in terminoloside and still containing asiaticoside is thus obtained.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]([CH3:18])([CH3:17])[CH3:16]>[Cl-].[Cl-].[Zn+2].[N+](C)([O-])=O>[CH3:16][C:15]([C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][C:8]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:9][CH:10]=3)([CH3:18])[CH3:17]
Reactant: CC(C)(C)Cl
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 500 mL three-necked round bottom flask equipped with an over head stirrer, nitrogen gas bubbler, and an addition funnel add 20.02 g (120.8 mmol) of carbazole, 49.82 g (365.5 mmol) of ZnCl2, and 300 mL of nitromethane at room temperature. To the resulting dark brown slurry add 49.82 g (365.5 mmol) of 2-chloro-2-methylpropane (also known as tertiary-butyl chloride or t-BuCl) dropwise from the addition funnel over the period of 2.5 hours. After completing the addition, stir the resulting slurry for an additional 18 hours. Pour the reaction mixture into 800 mL of ice cold water, extract with 3×500 mL methylene chloride, combine and dry the extracts with anhydrous magnesium sulfate, filter, and concentrate the filtrate first by rotary evaporation and then by evaporation under high vacuum to remove nitromethane. Dissolve the resulting residue first in hot methylene chloride (70 mL) followed by hot hexanes (50 mL), allow the resulting solution to cool to room temperature and then placed it in a refrigerator overnight. Isolate the solids formed and wash the isolated solids with cold hexanes and then place them under high vacuum to yield 10.80 g (32.0%) of (P1) as off white crystals.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.C1C(=O)N(Br)C(=O)C1.[N:73]1([C:81](=[S:83])[NH2:82])[CH2:78][CH2:77][S:76](=[O:80])(=[O:79])[CH2:75][CH2:74]1>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:83][C:81]([N:73]3[CH2:78][CH2:77][S:76](=[O:80])(=[O:79])[CH2:75][CH2:74]3)=[N:82][C:44]=2[C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)[CH:40]=[CH:39][N:38]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: NC(=S)N1CCS(=O)(=O)CC1
Agent: O=C1CCC(=O)N1Br
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=S1(=O)CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 90 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1.5 g, 3.40 mmol), NBS (0.60 g, 3.40 mmol) and 4-thiomorpholinecarbothioamide 1,1-dioxide (0.80 g, 4.12 mmol) the title compound of Step A was obtained (1.88 g, 90% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (br. s., 1H), 8.34 (d, J=5.1 Hz, 1H), 7.59-7.78 (m, 1H), 7.37-7.52 (m, 2H), 7.32 (t, J=7.7 Hz, 1H), 7.25 (t, J=9.1 Hz, 2H), 6.55 (d, J=4.9 Hz, 1H), 4.04 (br. s., 4H), 3.32 (br. s., 4H). m/z (ES+): 617 [M+H]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@@H:30]([NH:31][C:32]([C@@H:34]([NH:39][C:40]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[CH:46]=2)=[O:41])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:54])=[O:53])[CH2:25]1.O[C@H]1[C@H](NC([C@@H](NC(C2OC3C=CC=CC=3C=2)=O)CC(C)C)=O)CC[C@H](C)N(S(C2C=CC=CN=2)(=O)=O)C1>C(Cl)Cl>[CH3:37][CH:36]([CH3:38])[CH2:35][C@H:34]([NH:39][C:40]([C:42]1[O:43][C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[CH:46]=1)=[O:41])[C:32](=[O:33])[NH:31][C@H:30]1[CH2:29][CH2:28][C@@H:27]([CH3:51])[N:26]([S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=2)(=[O:53])=[O:54])[CH2:25][C:24]1=[O:23]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@@H]1CC[C@H](C)N(S(=O)(=O)c2ccccn2)C[C@H]1O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dess-Martin periodinane (1.0 g, 2.36 mmol) was added to a solution of benzofuran-2-carboxylic acid {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide and benzofuran-2-carboxylic acid {(S)-1-[(3R,4R,7S)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide (0.8 g, 1.48 mmol) in CH2Cl2 (20 ml) and was stirred at RT for 45 minutes. The solution was washed with 10% NaHCO3 and brine. Purification by colum chromatography (60% ethyl acetate/hexanes) gave the title compound as a mixture of diasteromers (0.75 g, 94%); The diastereomers were separated by HPLC. Diastereomer 1: 1H NMR: 8.72 (m, 1H), 8.0 (d, 1H), 8.92 (dd, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.42 (dd, 2H), 7.28 (d, 1H), 7.10 (d, 1H), 5.15 (m, 1H), 4.77 (d, 1H), 4.68 (m, 1H), 4.40 (m, 1H), 3.86 (d, 1H), 2.20–2.08 (m, 2H), 1.78–1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec: M+H+=541.2; Diastereomer 2: 1H NMR: 8.68 (m, 1H), 8.04 (d, 1H), 8.92 (dd, 1H), 7.68 (d, 1H), 7.58 (d, 2H), 7.52 (s, 1H), 7.42 (dd, 1H), 7.29 (d, 1H), 7.05 (m, 2H), 5.12 (m, 1H), 4.75–4.68 (m, 1H), 4.43 (m, 1H), 3.83 (d, 1H), 2.25–2.12 (m, 2H), 1.88–1.50 (m, 5H), 0.98 (m, 9H); Electrospray mass spec: M+H+=541.2.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([CH3:25])=[O:24])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:25][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:24]
Reactant: CS(=O)c1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1ccccc1C1CCNCC1
Yield: 83.9 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(2-methylsulfinylphenyl)piperidine (1.66 g) in 8 mL of trifluoroacetic acid was heated to reflux for 45 minutes. At the end of this period, the reaction mixture was evaporated and the residue was treated with toluene. Upon evaporating the solvent, the residue was treated with an additional portion of toluene and the process was repeated. The final residue was dried under reduced pressure and purified by chromatography; elution with dichloromethane:methanol:triethylamine (19:1:1) afforded the named product (0.87 g); MS: 224; NMR: 1.6-2.4 (m, 4), 2.7 (two peaks, 3), 2.9-3.2 (m, 3), 3.3-3.5 (m, 2), 5.3-5.7 (br, 1), 7.4-7.5 (m, 3), 7.9-8.0 (m, 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].S(=O)(=O)(O)O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Temperature: 8 °C
Reaction time: 1 h

Procedure:
A suspension of 5.11 g (20.0 mmol) of (1R,2S)-1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (commercially available from Synthetech Oregon, USA) in 1.94 mL of ethyl acetate was cooled to 8° C. using an ice bath. Then a solution of 2.17 g (21.0 mmol) of sulfuric acid in 4.0 mL of ethyl acetate was added in 5 min. The ice bath was removed and the reaction mixture was stirred for 30 min at room temperature and 1 h at 50° C. The reaction mixture was then cooled to room temperature and used in the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[C:19]([Si:23]([CH3:25])([CH3:24])[O:1][C@H:2]1[CH2:11][CH2:10][CH2:9][C@@:8]2([CH3:12])[C@H:3]1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@]12CCC[C@H](O)[C@@H]1CCCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@]2(C)C(=O)CCC[C@@H]12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2.3 g (12.6 mMol) of (4aR,5S,8aS)-5-Hydroxy-8a-methyl-octahydro-naphtalen-1-one in 63 ml of dimethylformamide are added under stirring and argon atmosphere 3.74 g (24.8 mMol) of tertio-butyl-dimethyl-silychloride and 1.94 g (28.5 mMol) of imidazole. The reaction mixture is heated to 100° C. for 4 hours, then additional 3.74 g of tert-butyl-dimethyl-silylchloride and 1.94 g of imidazole are added and the reaction mixture is kept overnight at 100° C. The reaction mixture is poured onto ice-water and extracted three times with diethylether. The combined organic extract is washed once with water and brine, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed over 250 g of silica gel with hexane/ethylacetate 9/1 to yield 3.17 g (85%) of low melting crystalline (4aR,5S,8aS)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-octahydro-naphtalen-1-one.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:11]([CH2:12][CH2:13][C@@:14]([OH:18])([CH:16]=C)C)[C@@:10](O)([CH3:19])[CH2:9][CH2:8][C@H:7]1[C:6]([CH3:22])([CH3:21])[CH2:5][CH2:4][CH2:3]2.O=[O+][O-].OO>>[CH3:16][C:14]1[O:18][C@@:2]2([CH3:1])[C@@H:11]([C@:10]3([CH3:19])[C@@H:5]([CH2:4][CH2:3]2)[C:6]([CH3:21])([CH3:22])[CH2:7][CH2:8][CH2:9]3)[CH2:12][CH:13]=1
Reactant: C=C[C@](C)(O)CC[C@@H]1[C@@]2(C)CCCC(C)(C)[C@@H]2CC[C@@]1(C)O
Agent: O=[O+][O-]
Agent: OO
Product: CC1=CC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O1

Procedure:
Sclareol is oxidised with ozone, followed by treatment with alkaline hydrogen peroxide to give sclareol oxide. The sclareol oxide is then oxidised with an organic hydroperoxide, preferably tert-butyl hydroperoxide, to give 12-acetyl-norlabdane oxide. The 12-acetyl-norlabdane oxide is converted to 12-acetoxy-norlabdane oxide by oxidation with an organic peracid, preferably peracetic acid. The 12-acetoxy-norlabdane oxide is then reduced to norlabdane oxide with sodium borohydride in the presence of a transition metal salt. The reaction scheme of EP 0882191A may be represented as follows:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH4+:10].[OH-]>O>[NH2:10][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)nc(Cl)n1
Reaction time: 0.5 h

Procedure:
A stirred suspension of cyanuric chloride (3.7 g, 30 mM) in water (25 mL) was treated with NH4OH (2.42 mL of a 28% solution diluted to 7.5 mL) at 0° C. Stirring was continued for 1 hr at 0° C. and 0.5 hr at 10° C. The product was filtered and rinsed with water until the filtrates were neutral. Drying (60° C., 0.2 mm) provided 2.84 g, (86%), mp=234°-235° C.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5]>C(O)(=O)C>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Yield: 69.3 %

Procedure:
1.46 Grams of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone were dissolved in 12 ml of an aqueous solution of acetic acid and the mixture was refluxed for 1 hour with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 1.27 g of 6(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =6.5 : 1) (purity: 74.7%). The yield was 69.3%. Percent recovery of the starting material was 11.4%.
Reaction SMILES: Br[C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6](=[O:23])[NH:7][C:8]1[S:9][C:10]2[CH2:16][CH2:15][O:14][C:13]3[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:12]=3[C:11]=2[N:22]=1)=[O:4].C(=O)([O-])[O-]>CN(C)C=O>[Br:21][C:18]1[CH:19]=[CH:20][C:12]2[C:11]3[N:22]=[C:8]([N:7]4[C:2]([CH3:25])([CH3:24])[C:3](=[O:4])[NH:5][C:6]4=[O:23])[S:9][C:10]=3[CH2:16][CH2:15][O:14][C:13]=2[CH:17]=1
Reactant: CC(C)(Br)C(=O)NC(=O)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 1.002 g (2.048 mmol) of 2-bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamide and 1.660 g (5.11 mmol) of ccesium carbonate in 100 ml of N,N-Dimethylformamide was stirred at 60° C. for 2 hours. The mixture was filtered, the filtrate concentrated in high vacuum, the residue partitioned between ethyl acetate and water. pH was adjusted to 5 by addition of 5% aq citric acid. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum to give 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione as an off-white powder which was used in the next steps without further purification. Yield 0.812 g (97%). MS (ESI+): 408.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1OC
Yield: 85.3 %

Procedure:
A solution of methyl 2-methoxy-5-nitrobenzoate (20.0 g, 0.097 mol) in methanol (300 mL) and 10% Pd/C (5.0 g) was stirred under hydrogen atmosphere under 70-80 psi pressure in Parr apparatus for 4-5 h. The reaction mass was filtered and the obtained filtrate was concentrated to afford 15.0 g of desired product. 1H NMR (300 MHz, DMSO de): δ 3.67 (s, 3H), 3.74 (s, 3H), 4.96 (br s, 2H), 6.75 (dd, J=2.4 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.92 (s, 1H); MS (in/z): 182.25 (M+H)+.