Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([NH2:20])=[NH:19])[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:9])[F:8].CN(C)[CH:24]=[CH:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=1)=O.[OH-].[Na+]>CC(O)C>[F:5][C:6]([F:21])([O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2[N:20]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)[CH:25]=[CH:24][N:19]=2)[CH:14]=[CH:15][CH:16]=1)[CH:7]([F:8])[F:9]
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Reactant: COc1cccc(C(=O)C=CN(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: COc1cccc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)c1
Temperature: 25 °C

Procedure:
21.28 g (84.7 mmol) of 3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl-guanidine nitrate are added to a solution of 17.4 g (84.7 mmol) of 3-dimethylamino-1-(3-methoxy-phenyl)-2-propen-1-one in 100 ml of 2-propanol. After the addition of 3.72 g (93.2 mmol) of sodium hydroxide, the reaction mixture is boiled under reflux for 21.3 h. After cooling to RT, the product is isolated by filtration and washed with 1-propanol and water. After drying at 60° under HV, N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(3-methoxy-phenyl)-2-pyrimidineamine is obtained; Rf =0.7 (methylene chloride:methanol =9:1), FAB-MS: 397 (M+ +1), m.p. 103°-104°.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>O.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]([C:38]1[N:39]=[N:40][C:41]([NH:44][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:42][CH:43]=1)=[O:37])[CH2:32]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nn1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)nn3)nc2n1C1CCCC1
Temperature: 120 °C
Yield: 58 %

Procedure:
In a 4 mL microwave vial 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (98 mg, 0.336 mmol), 3-(6-amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (112 mg, 0.336 mmol), BINAP (10.5 mg, 0.017 mmol), Cs2CO3 (164 mg, 0.504 mmol) and Pd(OAc)2 (3.8 mg, 0.017 mmol) were added together. The tube was capped and then purged with N2 three times. Dioxane (1.68 mL) was added and the capped tube was heated to 120° C. for 20 min in a microwave reactor. After cooling the reaction mixture was diluted with heptane resulting in the crude product precipitating out. The crude product was isolated by filtration, re-suspended in water and subjected to vigorous stirring and sonication. After re-isolating by filtration the product was purified by normal phase silica chromatography with a 0 to 20% MeOH/EtOAc gradient which gave a light tan solid (115 mg, 0.195 mmol). MS m/z 590.6 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=O)[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]>O=[Mn]=O>[CH3:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][C: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][CH3:18])=[O:20]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: O=[Mn]=O
Product: CCCCCCCCCCCCCCCCCC(=O)CCCCCCCCCCCCCCCCC

Procedure:
A mixture of plant oils (linseed, soybean, and rapeseed oils) was pretreated by hydrolysis and distillation to obtain fatty acid fractions according to carbon numbers. The C18 acid fraction thus obtained was used as the feed, the fraction being diluted with a paraffinic diesel fuel of biological origin. C18 acid content of the feedstock thus obtained was 31%, by weight. Double bonds of the feedstock were selectively prehydrogenated, and the stearic acid was continuously ketonised at atmospheric pressure, in a tubular reactor using a MnO2 catalyst. Temperature of the reactor was 370° C., the WHSV of total feed being 3 l/h. 22% by weight of 18-pentatriacontanone, or stearone, in a diluent was obtained as the ketonisation product.
Reaction SMILES: CC1(C)O[CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:19])[N:15]3[CH3:18])=[CH:10][C:9]=2[O:20][CH3:21])CO1.COC1C=C2C(=CC=1CC[N:37]1[CH2:42][CH2:41][CH:40]([N:43]3[C:51]4[C:46](=[CH:47][CH:48]=[C:49]([C:52]([NH2:54])=[O:53])[CH:50]=4)[CH:45]=[CH:44]3)[CH2:39][CH2:38]1)NC(=O)CC2>>[CH3:21][O:20][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[CH2:7][CH2:5][N:37]1[CH2:38][CH2:39][CH:40]([N:43]3[C:51]4[C:46](=[CH:47][CH:48]=[C:49]([C:52]([NH2:54])=[O:53])[CH:50]=4)[CH:45]=[CH:44]3)[CH2:41][CH2:42]1)[N:15]([CH3:18])[C:14](=[O:19])[CH2:13][CH2:12]2
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)N(C)C(=O)CC2
Reactant: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)NC(=O)CC2
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C)C(=O)CC2

Procedure:
The subject compound was synthesized from 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-2-one according to the method described in Example 56, (5).
Reaction SMILES: Br[C:2]1[N:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15]C)=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>CN(C=O)C.CCOC(C)=O.O.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>[CH2:26]([C:2]1[N:3]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:25]=[CH2:24]
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCc1c(CC(=O)OC)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 79.2 %

Procedure:
Argon was bubbled into a solution of tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (3.68 g, 9.66 mmol) in DMF (50 mL) for 1 h. Allyltributyltin (3 mL, 9.66 mmol) was added to the reaction mixture followed by the addition of Pd(PPh3)4 (1.1 g, 10 mol %). The reaction was heated at 80° C. for 6 h and then diluted with EtOAc and H2O. The entire solution was filtered over celite and to the solute was added 20% aqueous KH2PO4. The organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide tert-butyl 2-allyl-3-(2-methoxy-2-oxoethyl)-1H-indole-1-carboxylate (2.52 g, 76%). MS (m/z) 330 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:6]=[CH:5][N:4]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([SH:29])[C:23](=[CH:27][CH:28]=1)[C:24](O)=[O:25]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]2[C:24](=[O:25])[N:2]=[C:1]([C:3]3[CH:8]=[C:7]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH:6]=[CH:5][N:4]=3)[S:29][C:22]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccnc(C#N)c1
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Yield: 19.1 %

Procedure:
tert-Butyl 2-(2-cyano-4-pyridyl)ethylcarbamate (1.5 g, 6.0 mmol) and 4-chlorothiosalicylic acid (2.3 g, 12.1 mmol) were dissolved in pyridine (10 ml), and the mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.48 g, 19%) as white crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>>[CH2:19]([O:18][C:16]([NH:15][CH:9]1[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[O:12][CH2:11][CH2:10]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)OCCC2NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC1CCOc2cc(C(=O)O)ccc21)OCc1ccccc1
Yield: 93.3 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 8 using 4-(benzyloxycarbonylamino)chromane-7-carboxylic acid methyl ester (1.9 g) and 1N sodium hydroxide (14 ml), the objective 4-(benzyloxycarbonylamino)chromane-7-carboxylic acid (1.7 g) was obtained as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15]([OH:17])=O)[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[F:50][C:51]1[CH:52]=[CH:53][C:54]([NH2:57])=[N:55][CH:56]=1>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:57][C:54]3[CH:53]=[CH:52][C:51]([F:50])=[CH:56][N:55]=3)=[O:17])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: Nc1ccc(F)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol). The reaction mixture was stirred for 2 hours at 0° C. After this time, 5-fluoro-2-pyridinamine (146 mg, 1.3 mmol) was added to the mixture, which was then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the remaining residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organic phases were dried over sodium sulfate and concentrated. The remaining residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (350 mg, 0.78 mmol, 78% yield) as a yellow oil. MS: 447 ([M+H]+).
Reaction SMILES: CC1(C)[O:7][CH2:6][CH:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)[CH2:4][O:3]1.Cl>O1CCCC1>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][CH:5]([CH2:4][OH:3])[CH2:6][OH:7])=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: CC1(C)OCC(Nc2ccc3[nH]ncc3c2)CO1
Agent: Cl
Solvent: C1CCOC1
Product: OCC(CO)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
To a solution of the N-(2,2-dimethyl-1,3-dioxan-5-yl)-1H-indazol-5-amine (23 mg, 0.0930 mmol) obtained in Example 532 in tetrahydrofuran (1 ml) was added 1N-hydrochloric acid (1 ml), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction was terminated by the use of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate, whereby 2-(1H-indazol-5-ylamino)propane-1,3-diol (16 mg, 84%) was obtained.
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:25]([C:38]([OH:40])=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1.[NH2:51][C@H:52]([C:60]([O:62][CH3:63])=[O:61])[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@H:25]([C:38]([NH:51][C@H:52]([C:60]([O:62][CH3:63])=[O:61])[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:40])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:31][CH:32]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1

Procedure:
13 ml of N-ethylmorpholine and 22 g of DCC are added at 0° C. to a solution of 40.7 g (0.1 mmole) of Z-Tyr(But)-OH, 21.6 g of H-Phe-OMe hydrochloride and 13.5 g (0.1 mmole) of HOBt in 200 ml of dimethylformamide. The mixture is worked up as in the case of Example 1 a. The residue is triturated with petroleum ether and suction-drained. Yield 50.3 g (94%), melting point 103°-104° C., [α]D24 =-12.3° (c=1, methanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.S(=O)(=O)(O)O.N1C=CC=C1.[C:19](Cl)(=[O:21])[CH3:20].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:19]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)(=[O:21])[CH3:20]
Reactant: OCCn1cccc1
Reactant: CC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: c1cc[nH]c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCn1cccc1

Procedure:
Once the 1-(2-hydroxyethyl)pyrrole is obtained, it is esterified by any suitable means known in the art. For example, acetic acid is reacted with the 1-(2-hydroxyethyl)pyrrole in the presence of a strong acid such as sulfuric acid, and the reaction mixture is heated sufficiently to distill off the water that is formed as a result of the reaction. Preferably however, the pyrrole is reacted with acetyl chloride or acetic anhydride in a suitable solvent wherein there is a molar excess of the acetyl chloride or acetic anhydride. This reaction takes place at room temperature and will be completed in a relatively short period of time, with only an hour or two at the most being required for the reaction to reach completion. The 1-(2-acetoxyethyl)pyrrole is then isolated and purified by any means known in the art, such as extraction with a suitable organic solvent and removal of the solvent, to yield the desired compound represented by Formula (3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[CH2:12][CH2:13]Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(OCC)C>O1CCOCC1>[CH3:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[N:4][C:3]=2[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N
Reactant: ClCCc1nnc2ccccc2c1Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccccc1N1CCc2nnc3ccccc3c21

Procedure:
4-Chloro-3-(2-chloroethyl)cinnoline (1.52 g, 0.0067 mol) and o-toluidine (1.43 g, 0.0134 mol) in 1,4 dioxan (20 ml) were heated under reflux for 20 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and dilute sodium bicarbonate solution. The aqueous layer was extracted with chloroform (6×50 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a brown oil. The oil was purified by chromatography using chloroform (1 litre), chloroform/methanol (20:I) as eluant. The fractions containing the product were combined and evaporated under reduced pressure to give an oil. On trituration with diethyl ether a solid was obtained. The solid was collected by filtration and dried, 0.76 g. Recrystallization from ethyl acetate gave the title compound, 0.48 g, m.p. 140-142°.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][S:13](Cl)(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:24]=[C:25]1[CH2:30][NH:29][CH2:28][CH2:27][NH:26]1>ClCCl.N1C=CC=CC=1>[CH2:17]([CH:11]([CH2:12][S:13]([N:29]1[CH2:28][CH2:27][NH:26][C:25](=[O:24])[CH2:30]1)(=[O:15])=[O:14])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CN(S(=O)(=O)CC(Cc2ccccc2)C(=O)OCc2ccccc2)CCN1
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To the resultant compound from Example 11C (320.5 mg, 0.908 mmol) in dichloromethane (5 mL) at -10° C. was added 2-oxopiperazine (140 mg, 1.40 mmol, Yu et al. J. Med. Chem. 1900, 31, 1435) in pyridine (2 mL). After 30 min at -10° C. and 30 min at ambient temperature, the solvent was evaporated and the residue was partitioned between ether and 0.5 M H3PO4. The organic layer was washed with 0.5 M H3PO4, saturated NaHCO3 solution and brine, and then was dried over MgSO4 and evaporated. Chromatography of the residue on silica gel with 2% methanol in chloroform afforded 237.1 mg (63%) of the desired product as a foam: TLC (5% methanol/95% chloroform) Rf =0.26; 1H NMR (CDCl3) 7.43-7.07 (m, 10H), 5.97 (br, 1H), 5.12 (d, 1H), 5.08 (d, 1H), 3.82 (d, 1H), 3.78 (d, 1H), 3.55 (dd, 1H), 3.43-3.17 (m, 5H), 3.07 (dd, 1H), 3.01 (dd, 1H), 2.87 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][C@@H:14]([O:20]C(OCC)=O)[CH2:13][O:12][C:11](=[O:26])[C:10]2[C:27]([CH3:41])=[C:28]([O:39][CH3:40])[CH:29]=[C:30]([O:31][Si](C(C)(C)C)(C)C)[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4].Cl>C[O-].[Na+].CO>[CH3:1][O:2][C:3]([C@H:5]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15][C@@H:14]([OH:20])[CH2:13][O:12][C:11](=[O:26])[C:10]2[C:27]([CH3:41])=[C:28]([O:39][CH3:40])[CH:29]=[C:30]([OH:31])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: CCOC(=O)O[C@@H]1CCC(=O)N[C@H](C(=O)OC)CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OC[C@H](O)CCC(=O)N1
Yield: 35.9 %

Procedure:
A solution of 20 mg of (4R,9R)-16-(tert-butyl-dimethylsilanyloxy)-9-ethoxycarbonyloxy-14-methoxy-13-methyl-6, 12-dioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid methyl ester was subjected in an analogous manner to the procedure described in Example 1. The crude product was dissolved in 0.5 ml of a 0.6M solution of sodium methoxide in methanol. The solution was stirred at 0° C. for 7 min whereupon 2 ml of 1N hydrochloric acid were added. The mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to afford 5 mg of (4R,9R)-9,16-dihydroxy-14-methoxy-13-methyl-6,12-dioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][C:12]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([NH:22][C:10]1[C:9]([NH2:8])=[CH:14][CH:13]=[C:12]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(NC(=O)c2ccccc2C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1ccc(N)c(NC(=O)c2ccccc2C(C)(C)C)c1
Reaction time: 12 h
Yield: 98 %

Procedure:
To a mixture of N1-(t-butoxycarbonyl)-N2-(t-butylbenzoyl)-4-(ethoxycarbonylmethoxy)-1,2-benzenediamine (878 mg, 1.87 mmol) and CH2C12 (20 mL) was added TFA (1.5 mL, 19.5 mmol). After 12 h, the reaction was diluted with CH2Cl2 (300 ml) and washed with sat. aq. NaHCO3 (3×50 mL). The organic layer was MgSO4 dried, and concentrated. The crude material was chromatographed (65 g silica, 20% EtOAc/hexanes to 50% EtOAc/hexanes) to give the title compound (98%); IR(CHCl3): 1176, 1512, 1668, 1755, 2968 cm−1; NMR(300 MHz, DMSO-d6): 1.22 (t, 3H, J=7.2 Hz); 1.33 (s, 9H); 4.17 (q, 2H, J=7.2 Hz); 4.62 (s, 2H); 6.64 (d, 1H, J=8.7 Hz); 6.74 (d, 1H, J=8.7 Hz); 6.95 (d, 1H, J=3.0 Hz); 7.54 (d, 2H, J=8.7 Hz); 7.91 (d, 2H, J=8.1 Hz); 9.59 (s, 1H); MS(FD): 370.
Reaction SMILES: CN(C=O)C.[F:6][C:7]([F:20])([F:19])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[O:31][N:30]=1>O.CCOC(C)=O>[F:20][C:7]([F:19])([F:6])[C:8]1[C:16]([C:17]#[N:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][N:12]2[CH2:28][C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[O:31][N:30]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 90 °C

Procedure:
A DMF solution (25 mL) of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (2.66 mmol max) was treated with Cs2CO3 (1.73 g, 5.32 mmol) followed by 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.699 g, 2.66 mmol). The resulting suspension was heated to 90° C. for 30 min. The cooled reaction mixture was diluted with H2O (25 mL) and then extacted with EtOAc (3×25 mL). The pooled organic portions were washed with H2O and brine. Drying (Na2SO4) and filtration were followed by concentration. Column chromatography (SiO2, EtOAc/hexanes) afforded the title compound in excellent purity as a pale yellow solid (900 g, 75% over two stages): 1H NMR (DMSO-d6) δ 8.32 (d, J=6.0 Hz, 1H), 8.25 (bs, 1H), 8.11-8.06 (m, 2H), 7.98 (d, J=3.0 Hz, 1H), 8.86-8.81 (m, 2H), 6.82-6.81 (m, 1H), 5.95 (s, 2H).
Reaction SMILES: [O:1]1[CH:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)=[CH:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[O:19]1[C@@:5]23[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3][C@H:4]13
Reactant: C1=C2CCCCC2OCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C1CC[C@]23O[C@H]2CCOC3C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3,5,6,7,8,8a-hexahydro-2H-chromene (3.27 g, 23.66 mmol) in CH2Cl2 (75 mL) at 0° C. was added MCPBA (˜77%, 6.53 g, 28.4 mmol). The mixture was warmed to rt and stirred for 1 hr. The mixture was quenched with sat'd. aq. Na2SO3. The mixture was then partitioned between CH2Cl2 and sat'd. aq. NaHCO3. Extracted with CH2Cl2. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 3.85 (dd, 1H, J=7.8 Hz, 11.7 Hz), 3.54 (dd, 1H, J=4.6 Hz, 11.7 Hz), 3.31-3.38 (m, 1H), 3.19 (d, 1H, J=5.13 Hz), 2.15-2.24 (m, 1H), 1.75-1.97 (m, 4H), 1.52-1.72 (iii, 3H), 1.37-1.49 (m, 1H), 1.30-1.38 (m, 1H).