Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][C:15]1[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=1)[C:9]([C:26](=[O:37])[NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]1)=[CH:8]2)=[O:4].[Li+].[OH-]>C1COCC1.CO>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:10]3[C:11]4[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=4)[CH:8]=[C:9]3[C:26](=[O:37])[NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH:34]([CH3:35])[CH3:36])[CH2:30][CH2:29]3)[CH:19]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 70 °C

Procedure:
To a solution of 8.8 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid methyl ester in 200 ml THF and 100 ml methanol 58.5 ml of a 1 M aqueous LiOH solution were added and the mixture was heated to 70° C. for 4 h. After cooling to RT the organic solvents were removed under reduced pressure and the remaining aqueous solution was acidified with half concentrated HCl to pH 2. The precipitated product was collected by filtration. Yield: 7.9 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[C:5](=[O:18])[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[CH2:41][C:31]3([C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30][C:27]2=[N:28][CH:29]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH:20]([CH3:22])[CH3:21])[C:5](=[O:18])[N:6]([CH2:14][C:15]([NH:23][C:24]2[CH:25]=[C:26]3[CH2:41][C:31]4([C:39]5[C:34](=[N:35][CH:36]=[CH:37][CH:38]=5)[NH:33][C:32]4=[O:40])[CH2:30][C:27]3=[N:28][CH:29]=2)=[O:17])[C:7]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CC(C)Nc1nc(Cl)c(-c2ccccc2)n(CC(=O)O)c1=O
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc(Cl)c(-c2ccccc2)n(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [5-chloro-3-(isopropylamino)-2-oxo-6-phenylpyrazin-1(2H)-yl]acetic acid (74 mg, 0.23 mmol) [Parlow et al. (2003) J. Med. Chem. 46, 4050], (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol) [Wood et al. US 2007/265225], N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: O.[SH-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1Cl.Cl>CO>[Cl:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1[SH:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(S)c(Cl)c1
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A solution of sodium hydrosulfide hydrate (60 g technical; ~0.75 mol) in methanol (200 ml) is added to a solution of 3,4-dichloronitrobenzene (100.0 g; 0.52 mol) in methanol (750 ml) with cooling and at a rate to maintain the temperature of the reaction mixture below 40° C. After the addition is completed, the reaction mixture is stirred an additional 16 hours, and then poured on a mixture of ice and hydrochloric acid. The mixture remains strongly acidic. The precipitated yellow solid is filtered, washed and dried. This solid is purified by dissolving same in 25% aqueous sodium hydroxide, extracting the resultant solution several times with methylene chloride until the methylene chloride solution remains colorless. Next, concentrated hydrochloric acid is added to the aqueous solution dropwise to precipitate a light yellow solid and adjust the pH to 1-2. The thus formed slurry is filtered, the isolated solid is washed with water and dried to afford 52.6 g (55%) of title compound. A sample is recrystallized from cyclohexane, m.p. 77°- 78° C. Lit. 73.5°-74° C. (ref. Nippon Kagaku Kaishi 1972, 756).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:5][CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCC[C@@H](C)CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC[C@H](C)CCCC(C)C)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
A solution of 6.5 g (41 mmol) of (R)-3,7-dimethyl-1-octanol and 7.8 g (41 mmol) of p-toluenesulphonyl chloride in 50 ml of absolute chloroform is treated at 0° with 7.9 g (0.1 mol) of absolute pyridine. The mixture is subsequently stirred at 4° for 20 hours. For the working-up the mixture is poured on to 500 g of ice and extracted three times with chloroform. The combined organic phases are washed first with cold 1-N hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and subsequently with saturated aqueous common salt solution. After drying over potassium carbonate and removal of the solvent under reduced pressure, the crude product is chromatographed on 300 g of silicagel with benzene. There are obtained 11.4 g (89%) of (R)-3,7-dimethyl-1-octanol p-toluenesulphonate; [α]D20 =+2.0 (c=4.0, benzene).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1.[C:19]1([CH2:25][C:26]2[O:30][N:29]=[C:28]([CH2:31][CH2:32][CH2:33]O)[N:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:33][CH2:32][CH2:31][C:28]3[N:27]=[C:26]([CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:30][N:29]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: OCCCc1noc(Cc2ccccc2)n1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCn1c(=O)n(CCCc2noc(Cc3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.3 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3-propyl-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.74 mmol) in THF (4 ml) was treated with 3-[5-(phenylmethyl)-1,2,4-oxadiazol-3-yl]-1-propanol (195 mg, 0.89 mmol) and PPh3 (254 mg, 0.96 mmol). DBAD (223 mg, 0.96 mmol) was added in one portion and the mixture was left to stir at rt under nitrogen for 18 h. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified on a silica SPE column using a 0-70% cyclohexane/EtOAc gradient. The product fractions were combined, concentrated by high vacuum and purified on a silica SPE column using a 0-60% cyclohexane/EtOAc gradient. The product fractions were combined and concentrated then dissolved in anhydrous THF (4 ml). The solution was degassed by high vacuum then Pd(PPh3)4 (61 mg, 0.053 mmol) and morpholine (460 μl, 5.3 mmol) were added and the mixture left to stir at rt under nitrogen for 1 day. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated by high vacuum. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 2-4% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated to leave the title compound as a white solid (36 mg, 11%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[NH3:12].CO>O>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:12]
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: N
Solvent: O
Solvent: CO
Product: Nc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 51 %

Procedure:
To a pressure tube was added 1,3-difluoro-2-nitrobenzene (2.8 mL, 26.4 mmol) and 7 N NH3 in CH3OH (10 mL, 70 mmol). The tube was sealed and the mixture was stirred at room temperature for 5 days. The solution was diluted with H2O, extracted with CH2Cl2, and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give an oil. The oil was triturated with hexane and the resulting orange solid was collected by filtration to give the title compound (2.1 g, 51%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]3[N:25]=[CH:26][C:27]([C:28](O)=[O:29])=[C:17]3[N:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12].[OH:33][CH2:34][C:35]([NH:38][S:39]([C:42]1[S:43][C:44]([Cl:48])=[C:45]([NH2:47])[CH:46]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36]>>[Cl:48][C:44]1[S:43][C:42]([S:39](=[O:41])(=[O:40])[NH:38][C:35]([CH3:37])([CH3:36])[CH2:34][OH:33])=[CH:46][C:45]=1[NH:47][C:28]([C:27]1[CH:26]=[N:25][N:18]2[C:19]([C:21]([F:22])([F:24])[F:23])=[CH:20][C:15]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]([O:4][CH2:3][C:2]([F:32])([F:31])[F:1])[CH:6]=3)=[N:16][C:17]=12)=[O:29]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(OCC(F)(F)F)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.CS(N)(=O)=O.[C:64]([O:69][CH2:70][CH3:71])(=[O:68])/[CH:65]=[CH:66]/[CH3:67].S([O-])([O-])=O.[Na+].[Na+]>O.C(O)(C)(C)C>[O:22]1[C@H:66]([CH3:67])[C@H:65]1[C:64]([O:69][CH2:70][CH3:71])=[O:68]
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C/C(=O)OCC
Agent: CS(N)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H]1O[C@@H]1C
Temperature: 3 °C
Reaction time: 25 h
Yield: 50.4 %

Procedure:
AD-mix-β [Produced by ALDRICH company] (213 g) was added to a mixture of tert-butanol (760 ml) and water (760 ml). To the mixture was added methanesulfonamide (14.5 g). Under ice cooling, ethyl crotonate (17.4 g) was added, and the mixture was stirred for 5 hours at 0 to 6° C. and 25 hours at room temperature. Sodium sulfite (225 g) was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate (1 litter)for 22 hours by using liquid-liquid extraction apparatus. The ethyl acetate layer was taken, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether (300 ml), and insolubles were filtered off. The filtrate was concentrated under reduced pressure. To the residue was added 30% a solution of hydrogen bromide in acetic acid (125 ml), and the mixture was stirred for 1 hour at 45° C. After the mixture was cooled to room temperature, ethanol (280 ml) was added. The mixture was stirred for 21 hours at 45° C. and poured into a mixture of sodium hydrogencarbonate (168 g) and water (500 ml) under ice cooling with cautiously. The mixture was extracted five times with diethylether (200 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 ml). To the solution was added DBU (23.4 g). The mixture was stirred for 1 hour at room temperature, diluted with dichloromethane (300 ml) and washed with water (100 ml) and 0.5 N hydrochloric acid (200 ml). The aqueous layer was extracted twice with dichloromethane (50 ml). The dichloromethane layers were combined, and to the layer was added triethylamine (1 ml). The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to distillation under reduced pressure to give ethyl (2S,3R)-2,3-epoxybutanoate (10.0 g) as colorless liquid (Yield: 50%). Optical purity based on the analysis of HPLC of the product was 95% ee.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([OH:24])[CH2:20][CH2:21][C:22]#[CH:23].O.Cl>N1CCCCC1.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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]#[C:22][CH2:21][CH2:20][CH2:19][OH:24])=[C:14]([F:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(Br)c(F)cc21
Reactant: C#CCCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(C#CCCCO)c(F)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 455.2 %

Procedure:
A mixture of 3.04 g (9.67 mmol) 5-Bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester, 670 mg (0.58 mmol) Pd(PPh3)4, and 111 mg (0.58 mmol) CuI in 25 ml of piperidine was heated to 60° C., treated with 1.61 ml (1.80 mmol) 4-pentyne-1-ol and stirred at 80° C. for 2 hrs. After cooling to room temperature the mixture was poured into water, acidified with 2M aqueous HCl and extracted with EtOAc. Drying of the combined organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with CH2Cl2 gave 2.6 g (85%) of 6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butyl ester as a viscous orange oil, MS: 318 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])[NH2:24])=[C:14]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:13]=1[OH:38])(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([NH:24][C:1](=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])=[C:14]([CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:13]=1[OH:38])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(OCCCOc2cc(N)c(C)cc2Br)c(CCC(F)(F)F)c1O
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 12.3 ml of ethyl chlorooxalate in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 43.6 g of 3-{3-[4-acetyl-3-hydroxy-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-aniline and 15.3 ml of triethylamine in 400 ml of methylene chloride in the course of about 5 minutes and the mixture is then stirred at room temperature for a further 90 minutes. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether gives ethyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][CH:4]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:15](=[O:16])C1.ClCCl>CC#N>[F:12][C:2]([F:1])([F:11])[C:3]1[N:8]=[C:7]2[NH:9][C:15](=[O:16])[NH:10][C:6]2=[CH:5][CH:4]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccc(C(F)(F)F)nc1N
Solvent: CC#N
Solvent: ClCCl
Product: O=c1[nH]c2ccc(C(F)(F)F)nc2[nH]1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of the pyridine-2,3-diamine (160 mg, 0.9 mmol) from step (b) above and N,N′-disuccinimidyl carbonate (250 mg, 0.9 mmol, Aldrich) in MeCN (5 mL) was stirred at room temperature for 13 h. Another batch of N,N′-disuccinimidyl carbonate (125 mg, 0.5 mmol, Aldrich) was added and the reaction mixture was heated at 75° C. for 90 min. The reaction mixture was cooled to room temperature and dichloromethane (20 mL) was added. The precipitate was filtered and dried under vacuo to give the title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 204 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[O:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccccc5o4)cc3CC[C@@H]12
Yield: 45.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chlorobenzoxazole (71 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18h. 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 65 mg (45%) of the title compound as an amorphous foam. FDMS: m/e=378.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(=N)O[CH2:23][CH:24]=[CH2:25].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][NH:14][CH2:25][CH:24]=[CH2:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCNC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve Nα -(benzyloxycarbonyl)-β-(amino)-L-alanine, methyl ester (15.9g, 63mmol) in methylene chloride/cyclohexane (1:1, 600mL). Add allyl trichloroacetimidate (26g, 128mmol) and trifluoromethanesulfonic acid (5mL), 56.6mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give Nα -(benzyloxycarbonyl)-β-(allylamino)-L-alanine, methyl ester.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.CN(C)CCN(C)C.C([Li])CCC.[F:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>O.O1CCCC1>[F:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[OH:28])=[CH:25][CH:24]=1
Reactant: COCn1ccnc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of 11.2 g. (0.1 mol) of 1-(methoxymethyl)imidazole and 13.9 g. (0.12 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml. of anhydrous tetrahydrofuran 51 ml. (0.12 mol) of a butyllithium solution (20% in n-hexane) was added drop-wise over the course of one hour at -60° C., and under a nitrogen atmosphere. After the addition was completed, stirring was continued for another two hours. The cooling means was then removed and 25.1 g. (0.1 mol) of 4,4'-difluorobenzophenone in 150 ml. of anhydrous tetrahydrofuran were added drop-wise. The reaction mixture was stirred for 6 hours at room temperature and it was then decomposed with 15 ml. of water. The precipitated lithium hydroxide was filtered off and the filtrate was concentrated by distilling off the solvents. 2N Hydrochloric acid was added to the residue, after which the mixture was extracted with diethyl ether. The aqueous phase was made alkaline with 2N sodium hydroxide solution. The precipitate formed was filtered off, washed with water and twice crystallised from a mixture of isopropyl alcohol and petroleum ether (boiling range 40°-60° C.). α,α-Bis(p-fluorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. Melting point 133° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:7]1[C:3]([O:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:10])[N:6]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC1=NS(=O)(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) [prepared according to the procedure described in J. Org. Chem., 40, 2743 (1975)] in 200 ml of methanol at ambient temperature was added a solution of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine (from the dihydrochloride, 2.73 g; 11.2 mmoles) [prepared according to Belgian Pat. No. 779,775] in 25 ml of methanol. After stirring for 30 minutes, a methanolic solution of the title compound was produced. The TLC (Silica/CH2Cl2 :CH3OH (90:10)] gave Rf=0.44.