Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:45]=[C:44]([O:46][CH3:47])[C:38]2[O:39][CH2:40][CH2:41][CH2:42][O:43][C:37]=2[C:36]=1[F:48])=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[F:48][C:36]1[C:37]2[O:43][CH2:42][CH2:41][CH2:40][O:39][C:38]=2[C:44]([O:46][CH3:47])=[CH:45][C:35]=1[CH:21]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1)[C:20]1[NH:19][C:18](=[O:17])[N:1]([C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1F)OCCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c(F)c2c1OCCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
After adding 20 mg of 2-hydrazinopyrimidine and 50 ul of triethylamine to a solution of 103 mg of [2-(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 200 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (67 mg) as a light brown solid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:9]=2[CH:8]=1)=[O:6])[CH3:3].[Li]C(C)(C)C.CN([CH:33]=[O:34])C>C1COCC1>[OH:34][CH:33]1[C:24]2[CH:23]=[C:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:9]3=[CH:8][C:7]=2[C:5](=[O:6])[N:4]1[CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)NC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)N1C(=O)c2cc3c(cc2C1O)CCN(C(=O)OC(C)(C)C)CC3
Temperature: -40 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 1,1-dimethylethyl 7-{[(1-methylethyl)amino]carbonyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.95 g, 1 eq) in THF (50 ml), cooled to −78° C. under nitrogen atmosphere, t-BuLi (1.7 M pentane solution, 3.7 ml) was added over a 20 min period, then the mixture was allowed to warm to −40° C. and stirred for 1 h at that temperature. Anhydrous DMF (0.27 ml) was added dropwise, then the mixture was allowed to warm to room temperature and quenched with a saturated aqueous solution of NH4Cl (5 ml). After removal of THF, the residue was dissolved in ethyl acetate and the solution washed with 1 N HCl, 5% aqueous NaHCO3 and brine, then dried over Na2SO4 and concentrated to afford a white solid (1.0 g, 97% yield).
Reaction SMILES: F[B-](F)(F)F.[N:6]#[O+:7].[C:8]([O:12][C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.CCOC(C)=O>C(#N)C>[N:6]([N:15]([CH:16]1[CH2:18][CH2:17]1)[C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])=[O:7]
Reactant: CC(C)(C)OC(=O)NC1CC1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(N=O)C1CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 106.7 %

Procedure:
Nitrosonium tetrafluoroborate (9.32 g, 79.8 mmol) was added carefully in several portions to a cooled (−30° C.) solution of N-(tert-butoxycarbonyl)cyclopropylamine (9.57 g, 60.9 mmol) and anhydrous pyridine (11.7 mL) in dry acetonitrile (150 mL). The solution was stirred at −30° C. for 30 minutes, and then at 0° C. for 2 hours. Ice water and EtOAc were added and the organic phase was separated and washed quickly with 1N HCl to remove pyridine. The organic phase was washed with 1N NaHCO3 and brine, dried (MgSO4), filtered, and evaporated under high vacuum with a water bath temperature below 40° C. to give N-nitroso-N-(tert-butoxycarbonyl)amino-cyclopropane (12.1 g, quantitative) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH2:38]([N:45]1[CH2:49][CH2:48][C@@H:47]([NH2:50])[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:38]([N:45]1[CH2:49][CH2:48][C@@H:47]([NH:50][C:30]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][C:18]=2[N+:23]([O-:25])=[O:24])=[O:36])[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N[C@@H]4CCN(Cc5ccccc5)C4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
Chloroform (27 ml) and triethylamine (4 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (200 mg) to prepare a solution. Triphosgene (192 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3R)-(−)-1-Benzyl-3-aminopyrrolidine (77 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (184 mg, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:34])[CH:6]=1.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:34])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](CC3CCCCC3)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
A solution of ((S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-propionamide (prepared in Example 62, 201 mg, 0.37 mmol) in tetrahydrofuran (6 mL) was treated with 1N aqueous hydrochloric acid (3 mL). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. Upon concentration afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-((R)-2,3-dihydroxy-propyl)-1-H-pyrazol-3-yl]-propionamide (153 mg, 83%) as a white powder: HR-ES-MS m/z calculated for C25H31ClN4O5, [M+H]+ 503.2056 observed 503.2056; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-1.02 (m, 2H), 1.02-1.29 (m, 4H), 1.52-1.83 (m, 7H), 3.18-3.32 (m, 2H), 3.70-3.93 (m, 2H), 4.09 (dd, J=13.6, 3.6 Hz, 1H), 4.19 (d, J=18.4 Hz, 1H), 4.59 (d, J=18.4 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H), 4.80 (s, 1H), 4.85-4.92 (m, 1H), 4.94 (d, J=5.4 Hz, 1H), 6.40 (d, J=1.8 Hz, 1H), 7.37 (td, J=7.8, 1.5 Hz, 1H), 7.46 (t, J=7.2 Hz, 1H), 7.50-7.56 (m, 2H), 7.65 (d, J=7.8 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C(N(CC)CC)C.Cl>ClCCl.O>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1ccc(C(=O)Cl)c(Cl)c1
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)cc1Cl
Reaction time: 24 h

Procedure:
1.25 g (6.61 mmol) of 2-chloro-4-methylbenzoyl chloride in 4 ml of dichloromethane were mixed with 0.84 g (8.60 mmol) of N,O-dimethylhydroxylamine hydrochloride and 2.4 ml (17.2 mmol) of triethylamine and stirred for 24 h. Water and 1N hydrochloric acid were added to the reaction mixture, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 1.10 g (78% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:44])[CH2:40][CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:44][CH:39]([CH2:38][CH3:37])[CH2:40][CH2:41][CH2:42][CH3:43])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCC(O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 64 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-heptanol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (46 mg, yield 61%).
Reaction SMILES: C(S)C.[H-].[Na+].CN(C=O)C.[S:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=4)[CH:22]=[N:21][C:20]=23)=[CH:12]1>O>[S:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)[CH:22]=[N:21][C:20]=23)=[CH:12]1
Reactant: COc1ccc(-c2cnc3c(-c4ccsc4)cnn3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cnc3c(-c4ccsc4)cnn3c2)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 23.4 %

Procedure:
Ethanethiol (30 mg, 36 uL) was added dropwise over 1 min to a suspension of sodium hydride (23 mg, 0.98 mmol) in 10 dry DMF (2 mL) under argon. After 15 min, the compound of example 2 (50 mg, 0.16 mmol) was added and the reaction mixture was heated at 150° C. for 1.5 h. The resulting brown solution was cooled, poured into water (25 mL) and washed with ethyl acetate (2×25 mL). The combined organics were dried (Na2SO4), is concentrated, and purified by flash chromatography (40% EtOAc/Hexanes) to give the title compound as a yellow solid [11 mg, 23%, Rf=0.12 (40% EtOAc/Hexanes)]: 1H NMR (CD3OD) δ8.96 (d, 1H, J=2.4Hz), 8.85 (d, 1H, J=2.2Hz), 8.44 (s, 1H), 7.94 (dd, 1H, J=2.9, 1.2Hz), 7.74 (dd, 1H, J=4.9, 1.2Hz), 7.56 (d, 2 H, J=8.8Hz), 7.46 (dd, 1H, J=4.9, 2.9Hz), 6.94 (d, 2H,J=8.6Hz).
Reaction SMILES: [CH3:1][C:2]1[C:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:24])([CH2:13][CH2:14]2)[C@@H:8]([C:9](=[O:11])[CH3:10])[CH:7]([CH2:25]SC2C=CC=CC=2)[CH2:6]3)[CH:3]=1.C1(C)C=CC=CC=1.CO.C[O:43]P(OC)OC>C(N(CC)CC)C>[OH:43][C@:8]1([C@:12]2([CH3:24])[C@H:5]([C@H:4]3[C@H:15]([CH2:14][CH2:13]2)[C@:16]2([CH3:23])[C:21](=[CH:20][C:19](=[O:22])[CH2:18][CH2:17]2)[C:2]([CH3:1])=[CH:3]3)[CH2:6][C:7]1=[CH2:25])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)[C@H]1C(CSc2ccccc2)C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: C=C1C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
6-Methyl-16-(phenylsulfenylmethyl)-pregna-4,6-diene-3,20-dione (VIA, Example 22, 150 mg), toluene (1.25 ml), methanol (0.216 ml), triethylamine (0.011 ml) and finally trimethylphosphite (0.076 ml) were added to a vial which was sealed, stirred and heated at 100° for 4.75 hr. The mixture was concentrated under reduced pressure to an oil which is TLC'd on silica gel eluting with acetone/methylene chloride (5/95) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:34])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C)C=O>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:34])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Sc2ccc(O)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Sc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]-carbamate (195 mg) and potassium carbonate (59 mg) in N,N-dimethylformamide (3 ml) was added tert-butyl bromoacetate (84 mg), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give tert-butyl [4-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]-phenoxy]acetate (168 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH2:8][CH2:9][CH3:10].[C:24]([O-])(=[O:26])C.[Na+]>CN(C)C=O>[CH:24]([C:20]1[CH:21]=[CH:22][C:23]2[N:11]([CH:6]=[CH:7][CH2:8][CH2:9][CH3:10])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:26]
Reactant: CC(=O)[O-]
Reactant: CCCC=Cn1c2ccccc2c2ccccc21
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCC=Cn1c2ccccc2c2cc(C=O)ccc21
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (9.1 g, 60 mmol) was added to dimethylformamide (17 mL) at 0° C. with strong stirring over 15 minutes. Upon complete addition, the orange solution was stirred at 0° C. for a further 10 minutes. N-pentenyl-carbazole (10.5 g, 45 mmol) was gradually added to the iminium salt and the mixture was heated at 100° C. for 1.5 hours, then cooled to room temperature and added to ice. The ice slurry was adjusted to a pH of 6 with saturated sodium acetate solution and the crude product was extracted with dichloromethane (2×50 mL), dried (Na2SO4), and concentrated. Traces of dimethylformamide were removed under high vacuum to give 9.6 g of 3-formyl-N-pentenyl-carbazole as a brown oil. The material was used at this level of purity in the next step of the synthesis.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Br:11])[C:4]=2[N:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:30]1[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[N:6]([C@@H:30]2[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]2[O:32][C:33](=[O:35])[CH3:34])[C:5]2[CH:7]=[C:8]([Cl:13])[C:9]([Cl:12])=[C:10]([Br:11])[C:4]=2[N:3]=1
Reactant: Clc1cc2[nH]c(Br)nc2c(Br)c1Cl
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2c(Br)c(Cl)c(Cl)cc21
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a suspension of 2,4-dibromo-5,6-dichloro-1H-benzimidazole (0.35 g, 1 mmol), in acetonitrile (5 mL) was added N,O-bis(trimethylsilyl)acetamide (0.25 mL, 1 mmol). The resulting mixture was allowed to stir at 70° C. for 15 min, followed by the addition of 1,2,3-tri-O-acetyl-5-deoxyribofuranose (0.31 g, 1.2 mmol) in acetonitrile (5 mL) and trimethylsilyltrifluoromethane sulfonate (0.25 mL, 1.3 mmol). The mixture was allowed to stir at 70° C. for 30 min and was then allowed to cool to RT. The mixture was diluted with ethyl acetate, washed with a saturated aqueous NaHCO3 solution, dried over NaSO4 and the solvents were removed by rotary evaporation. The product was purified by flash chromatography using methylene chloride then 1:1 methylene chloride/chloroform followed by recrystallization from methanol to provide 0.35 g (63%) of the title compound as white crystals: m.p. 152-154° C.; 1H NMR (DMSO-d6) δ: 8.16 (s, 1H), 6.15 (d, 1H), 5.63 (t, 1H), 5.27 (dd, 1H), 4.26 (m, 1H), 2.13 (s, 3H), 2.02 (s, 3H), 1.51 (d, 3H).
Reaction SMILES: [C:1]([N:3]=[C:4]([S-:6])[S-:5])#[N:2].[K+].[K+].S(OCC)(O[CH2:13][CH3:14])(=O)=O.[OH:18]O>>[OH:18][C:1]1[N:3]=[C:4]([S:6][CH2:13][CH3:14])[S:5][N:2]=1
Reactant: OO
Reactant: CCOS(=O)(=O)OCC
Reactant: N#CN=C([S-])[S-]
Agent: [K+]
Product: CCSc1nc(O)ns1

Procedure:
Dipotassium N-cyano-dithioimidocarbonate and diethyl sulfate were condensed in an aqueous media and the product was reacted with hydrogen peroxide to obtain 3-hydroxy-5-ethylthio-1,2,4-thiadiazole melting at 129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[C@H:16]([CH3:17])[CH2:15][O:14][C:13]1=[O:18])[C:6]([OH:8])=O.[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[ClH:19].[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:6]([C:5]3[CH:9]=[CH:10][C:11]([N:12]4[C@H:16]([CH3:17])[CH2:15][O:14][C:13]4=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:8])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COc1cc(C(=O)O)ccc1N1C(=O)OC[C@H]1C
Agent: Cl
Product: COc1cc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)ccc1N1C(=O)OC[C@H]1C
Yield: 45.7 %

Procedure:
By reaction and treatment in the same manner as in Example 87 and using (R)-3-methoxy-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (1 g) described in Preparation Example 46 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (956 mg) described in Preparation Example 64, the title compound (838 mg) was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C([Si](C)(C)[O:16][CH:17]([CH2:42][C:43](=[O:54])[NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[CH2:18][CH:19]([OH:41])[CH2:20][CH2:21][CH:22]1[CH:31]2[C:26](=[CH:27][CH:28]([CH3:39])[CH2:29][CH:30]2[O:32][C:33](=[O:38])[CH:34]([CH3:37])[CH2:35][CH3:36])[CH:25]=[CH:24][CH:23]1[CH3:40])(C)(C)C.CCN(CC)CC>C(Cl)Cl>[OH:16][CH:17]([CH2:42][C:43](=[O:54])[NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[CH2:18][C:19](=[O:41])[CH2:20][CH2:21][CH:22]1[CH:31]2[C:26](=[CH:27][CH:28]([CH3:39])[CH2:29][CH:30]2[O:32][C:33](=[O:38])[CH:34]([CH3:37])[CH2:35][CH3:36])[CH:25]=[CH:24][CH:23]1[CH3:40]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(CC(=O)NCc3ccc(OC)cc3)O[Si](C)(C)C(C)(C)C)C21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(=O)CC(O)CC(=O)NCc3ccc(OC)cc3)C21
Reaction time: 2 h

Procedure:
A solution of 0.18 ml oxalyl chloride in 10 ml CH2Cl2 is slowly treated at −60° C. with 0.33 ml DMSO. After 15 minutes stirring at −60° C. a cold solution (−78° C.) of 2-methyl-butyric acid 8-[5-(tert-butyl-dimethyl-silanyloxy)-3-hydroxy-6-(4-methoxy-benzylcarbamoyl)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml CH2Cl2 is added. After 2 hours at −60° C., 0.80 ml of NEt3 is added and the temperature is slowly rised to room temperature. After 2 hours at room temperature the reaction is quenched with H2O. The phases are separated and the organic phase dried and concentrated. The crude product is purified by silica gel chromatography (CH2Cl2/MeOH). The resulting compound is dissolved in THF and treated with AcOH and Bu4NF.3H2O. After 30 hours the reaction mixture is concentrated, diluted with AcOEt and washed with H2O, sat. NaHCO3, brine, then dried (Na2SO4) and concentrated. The crude product is purified by silica gel chromatography. Pure fractions are combined and evaporated to afford 2-methyl-butyric acid 8-[5-hydroxy-6-(4-methoxy-benzylcarbamoyl)-3-oxo-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester as foam.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:27])[CH2:4][O:5][C:6]1[C:14]([Br:15])=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:16][C@@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[CH:8][CH:7]=1.[CH:28]([O:30][CH2:31][CH3:32])=[CH2:29]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:15][C:14]1[C:6]([O:5][CH2:4][CH:3]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[CH2:2][Br:1])=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:16][C@@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH3:18])[N:11]=[CH:10]2
Reactant: C[C@@H](Cn1ncc2ccc(OCC(O)CBr)c(Br)c21)O[Si](C)(C)C(C)(C)C
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(C)OC(CBr)COc1ccc2cnn(C[C@H](C)O[Si](C)(C)C(C)(C)C)c2c1Br
Yield: 85.1 %

Procedure:
To a solution of the product from Step E (1.85 g, 3.54 mmol) and p-toluenesulfonic acid (0.01 g) in dichloromethane (50 mL) at 0° C. was added ethyl vinyl ether (1 mL, 10.5 mmol). After 30 min the reaction was quenched with a saturated solution of sodium bicarbonate (50 mL) and extracted with EtOAc (3×80 mL). Evaporation and purification by chromatography (silica, 1% to 8% EtOAc/hexane) gave a viscous oil (1.79 g, 81%): LC/MS (+APCI) m/z 595 (M+H).