Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9]2)[C:3]([OH:5])=O.S(Cl)(Cl)=O.C(N(CC)CC)C.[F:30][C:31]1[C:32]([NH:43][NH2:44])=[N:33][CH:34]=[C:35]([C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)[CH:36]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CO.CN(C=O)C>[F:18][C:2]([F:1])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([O:16][CH3:17])=[CH:9]2)[C:3]([NH:44][NH:43][C:32]1[C:31]([F:30])=[CH:36][C:35]([C:37]2[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=2)=[CH:34][N:33]=1)=[O:5]
Reactant: COc1cnc2ccc(C(F)(F)C(=O)O)cc2c1
Reactant: Cn1cc(-c2cnc(NN)c(F)c2)cn1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COc1cnc2ccc(C(F)(F)C(=O)NNc3ncc(-c4cnn(C)c4)cc3F)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A round bottom flask was charged with 2,2-difluoro-2-(3-methoxyquinolin-6-yl)acetic acid (389 mg, 1536 μmol) and DMF (8 mL). The solution was cooled to 0 C, thionyl chloride (224 μl, 3073 mmol), was added and the resulting solution was maintained 1 h at 0° C. Then, triethylamine (641 μl , 4609 μmol) was added via syringe, followed by 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (382 mg, 1844 μmol) and 4-(dimethylamino)pyridine (18.8 mg, 154 μmol); both added as solids. The heterogeneous solution was stirred at 0° C. for 1 h, then allowed to warm to rt and stir for 18 h. The mixture was quenched with saturated aqueous NaHCO3 (50 mL) and the resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were concentrated (heating to 50° C.) and the residue purified by SiO2 chromatography solvent system: CH2Cl2:MeOH 99%:1% gradient 90:10 CH2Cl2 to yield 2,2-difluoro-N′-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-methoxyquinolin-6-yl)acetohydrazide (225 mg, 33.1% yield) as a brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].[CH3:33][C@H:34]1[CH2:36][O:35]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:33][C@@H:34]([OH:35])[CH3:36])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: C[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C[C@H](C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.5 %

Procedure:
(S)—N-(1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1H-imidazole-4-carboxamide (0.271 mmol, 100 mg) and potassium carbonate (2.71 mmol, 375 mg) were dissolved in dry DMF (3 ml) under nitrogen atmosphere. (S)-2-methyl-oxirane (0.298 mmol, 0.021 ml) was added and the resulting mixture was stirred for 2.5 h at RT. The mixture was heated to 60° C. for two days during which more (S)-2-methyloxirane (0.252 ml) was added. The solvent was evaporated and the residue was purified by flash chromatography. 63 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.05 (d, 3H), 1.07 (d, 3H), 2.34 (s, 3H), 3.67-3.93 (m, 3H), 4.20-4.50 (m, 3H), 4.92 (bs, 1H), 6.95 (d, 1H), 7.47 (s, 1H), 7.83 (d, 1H), 7.98-8.00 (m, 2H), 8.04 (d, 1H), 8.11-8.12 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl[C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1[CH:18]=[O:19]>CN(C)C=O>[CH3:16][N:15]1[C:11]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[C:12]([CH:18]=[O:19])[C:13]([CH3:17])=[N:14]1
Reactant: Oc1ccccn1
Reactant: Cc1nn(C)c(Cl)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Oc2ccccn2)c1C=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 7.9 %

Procedure:
Under a nitrogen gas atmosphere, 3.0 g (0.032 mole) of 2-hydroxypyridine was added at 25° C. to 30 ml of a N,N-dimethylformamide solution containing 1.92 g (0.048 mole) of sodium hydroxide. Then, 5.1 g (0.032 mole) of 5-chloro-1,3-dimethyl-4-formylpyrazole in 20 ml of N,N-dimethylformamide was added to the mixture solution at 25° C. The reaction mixture was heated to 100° C. and stirred at 100° C. for 4 hours. The reaction mixture was then poured into 300 ml of ice water and extracted with two 100-ml portion of ethyl acetate. The organic layers were combined, washed once with 100 ml of saturated aqueous sodium chloride solution and dried over unhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel to obtain 0.55 g of 1,3-dimethyl- 5-(2-pyridyloxy)-4-formylpyrazole.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.P(O)(O)(O)=O.[NH2:16][OH:17].[OH-].[NH4+]>O>[CH3:1][C:2]([NH:16][OH:17])=[C:4]1[CH:5]=[CH:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(NO)=C1C=CC(=O)C=C1
Yield: 211.8 %

Procedure:
A solution was prepared by adding 20.4 g (0.15 mol) of 4-hydroxyacetophenone and 12.9 g (65.6 mmol) of hydroxylamine phosphate to 100 mL of water at 70° C. To the solution was added 16.3 mL of 30% ammonium hydroxide which was then heated at reflux for 0.5 h. White crystals formed upon cooling yielding 21.0 g (92.6%) of 4-hydroxyacetophenone oxime.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][C:9]([CH3:33])([CH3:32])[C@H:10]([NH:19][C:20](=[O:31])[C@@H:21]([CH2:26][N:27]([CH:29]=[O:30])[OH:28])[CH2:22][CH2:23][CH2:24][CH3:25])[C:11](C1N(C)C=CN=1)=[O:12]>>[CH3:32][C:9]([CH3:8])([CH3:33])[C@H:10]([NH:19][C:20](=[O:31])[C@@H:21]([CH2:26][N:27]([CH:29]=[O:30])[OH:28])[CH2:22][CH2:23][CH2:24][CH3:25])[C:11]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: CCCC[C@H](CN(O)C=O)C(=O)N[C@H](C(=O)c1nccn1C)C(C)(C)C
Reactant: Brc1ccccn1
Product: CCCC[C@H](CN(O)C=O)C(=O)N[C@H](C(=O)c1ccccn1)C(C)(C)C

Procedure:
The title compound was prepared from 2-bromopyridine as outlined in Scheme 2, in an analogous manner to 2(R)-[(N-formyl-N-hydroxyamino)-methyl]-hexanoic acid-[2,2-dimethyl-1(S)-(1-methyl-1H-imidazole-2-carbonyl)-propyl]-amide. The relevant spectroscopic data are described below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][C@@H:31]([OH:33])[CH3:32].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[NH:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][C@@H:31]([OH:33])[CH3:32]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC[C@H](C)O)c3cc2Br)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@H](O)CNc1ncnc2cc(OCc3cccc(S(C)(=N)=O)c3)c(Br)cc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
According to GWP 6, (RS)-S-(3-{[(6-bromo-4-{[(S)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide (39 mg, 0.073 mmol) is dissolved in ethanol (5 mL), admixed with sodium ethoxide (18 mg, 0.26 mmol) and stirred at 60° C. for 6 hours. The reaction solution is admixed with saturated sodium bicarbonate solution and extracted with ethyl acetate. Drying of the organic phase over sodium sulphate and removal of the solvent and also chromatographic purification of the residue (silica gel, dichloromethane/methanol: 0→10% methanol) gives the desired product in 86% yield (29 mg).
Reaction SMILES: OCC[CH:4]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])(C)C)[CH:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.O1CCCC1.CC(C)([O-])C.[K+]>C(OCC)(=O)C>[O:9]1[C:8]2([CH2:7][CH2:6][CH:5]([CH:4]3[CH2:21][CH2:18][O:17][C:16](=[O:22])[NH:15]3)[CH2:14][CH2:13]2)[O:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC(CCO)C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1NC(C2CCC3(CC2)OCCO3)CCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
A 250 mL round bottom flask was charge with tert-butyl (3-hydroxy-1-(1,4-dioxaspiro[4.5]decan-8-yl)propyl)carbamate (2.11 g, 6.69 mmol) and tetrahydrofuran (134 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (900 mg, 8.03 mmol) was added. The mixture was stirred at 0° C. for 2 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. Dry organic layer with MgSO4, filter, and concentrate in vacuo to give 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1,3-oxazinan-2-one (1.39 g, 5.76 mmol) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:14]/[N:15]([CH3:17])[CH3:16])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CN(C)/C=C/c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 1-methyl-2-nitro-4-bromobenzene (17) (29.86 g, 138.2 mmol) in toluene (200 mL) was added dimethylformamide dimethylacetal (17.52 g, 138.2 mmol). The mixture was heated to reflux for 14 hours. After cooling to room temperature the mixture was concentrated under vacuum and the resulting oil was immediately used in the next reaction.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1>CO.[Pd]>[OH:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](Oc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: O[C@@H]1CNCC[C@H]1Oc1ccccc1

Procedure:
8.2 g (0.025 mol) of trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-piperidine are dissolved in 140 ml of methanol and hydrogenated in the presence of 0.8 g of a 5% strength palladium-on-charcoal catalyst under normal pressure and at room temperature. After the absorption of hydrogen has ceased, the catalyst is filtered off by means of diatomaceous earth and the filtrate is evaporated under a water pump vacuum. The crude base crystallies from methanol/ether and gives trans-3-hydroxy-4-phenoxy-piperidine with a melting point of 134°-136°. The neutral fumarate prepared therefrom with fumaric acid crystallises from methanol/ether; melting point 180°-183°.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C:16]([O:20][CH3:21])([O:18][CH3:19])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])(=O)C.N>>[SH:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C:16]([O:20][CH3:21])([O:18][CH3:19])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CCCSC(C)=O)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CCCS)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield 1-(4-mercapto-1-oxobutyl)-4,4-dimethoxy-L-proline.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([O:22][CH2:23][C:24]=1[CH:25]=[CH:26]N(C)C)[CH:20]([NH:30][C:31](=[O:61])[C:32](=[N:58][O:59][CH3:60])[C:33]1[N:34]=[C:35]([NH:38][C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[S:36][CH:37]=1)[C:19]2=[O:62])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=[O:66])C>>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([O:22][CH2:23][C:24]=1[CH2:25][CH:26]=[O:66])[CH:20]([NH:30][C:31](=[O:61])[C:32](=[N:58][O:59][CH3:60])[C:33]1[N:34]=[C:35]([NH:38][C:39]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[S:36][CH:37]=1)[C:19]2=[O:62])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CN(C)C)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A solution of the E form of the syn isomer of 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (1.05 g) in ethyl acetate (10 cc) is stirred vigorously for 1 hour at 20° C., in the presence of a 1 N solution of hydrochloric acid (5 cc). The mixture is separated by decantation and the organic phase is washed with a saturated solution of sodium bicarbonate (10 cc), distilled water (10 cc) and a saturated solution of sodium chloride (10 cc). The ethyl acetate phase is dried over anhydrous magnesium sulphate and filtered and the filtrate is concentrated to dryness at 30° C. under reduced pressure (20 mm Hg; 2.7 kPa). This yields the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-(2-oxoethyl)-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (1.00 g) in the form of a hard yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:36][CH3:37])=[C:22]([CH:35]=3)[CH2:23][N:24]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1O.C(OC(N1CCC(N(CC2C=C(C3C=CN=C(Cl)N=3)C=CC=2OC)S(C)(=O)=O)CC1)=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:36][CH3:37])=[C:22]([CH:35]=3)[CH2:23][N:24]([CH:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)[S:25]([CH3:28])(=[O:26])=[O:27])[CH:15]=[CH:14][N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2ccnc(NCCc3ccc(O)c(F)c3)n2)cc1CN(C1CCNCC1)S(C)(=O)=O
Agent: COc1ccc(-c2ccnc(Cl)n2)cc1CN(C1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Product: COc1ccc(-c2ccnc(NCCc3cccc(F)c3)n2)cc1CN(C1CCNCC1)S(C)(=O)=O

Procedure:
(N-(5-{2-[2-(3-Fluoro-4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-benzyl)-N-piperidin-4-yl-methanesulfonamide: Intermediate 88 was coupled with intermediate 83 following procedure F. The resulting product was deprotected following procedure G. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 530. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 7.9 (d, 1H), 7.0 (m, 2H), 7.0 (m, 3H), 6.8 (m, 2H), 4.3 (s, 2H), 3.9 (s, 3H), 3.5 (d, 2H), 3.0 (s, 3H), 2.7 (m, 6H), 2.6 (m, 1H), 1.7-1.5 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:12]=O)=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#[N:16].[Na+]>CO>[C:1]1([C:7]2[C:8]([CH2:12][NH2:16])=[CH:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1cocc1-c1ccccc1
Agent: [Na+]
Solvent: CO
Product: NCc1cocc1-c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 20.8 %

Procedure:
Prepare a solution of 4-phenyl-3-formylfuran (1.36 g, 7.91 mmol) in methanol (35 mL). Add NH4OAc (6.1 g, 79.1 mmol) and NaCNBH3 (348 mg, 5.54 mmol). Stir the reaction mixture at room temperature under nitrogen for 2.5 days then concentrate the mixture, dilute with water (50 mL), basify with 1 N sodium hydroxide, and extract with methylene chloride (2×100 mL). Dry the organic phase (Na2SO4), filter, and concentrate. Perform flash chromatography on silica gel eluting with 9:1 ethyl acetate/MeOH followed by 100% MeOH to afford 200 mg of the title compound. 1H NMR (CDCl3) δ 7.52 (s, 1H), 7.30-7.46 (m, 6H), 3.87 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([N:12]([CH3:18])[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:11])=[O:10].Cl[C:20]([O:22][CH2:23][CH2:24][Br:25])=[O:21]>CC(C)=O>[CH3:8][S:9]([N:12]([CH3:18])[N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:20]([O:22][CH2:23][CH2:24][Br:25])=[O:21])(=[O:10])=[O:11]
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Reactant: O=C(Cl)OCCBr
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(N(C(=O)OCCBr)S(C)(=O)=O)S(C)(=O)=O
Reaction time: 18 h

Procedure:
1,2-Bis(methylsulfonyl)-2-(2-bromoethoxycarbonyl)-1-methylhydrazine (compound 8) was synthesized as follows: Triethylamine (1.45 g, 0.014 mol) was added in portions to a stirred solution of 1,2-bis(methylsulfonyl)-1-methylhydrazine (2.02 g, 0.01 mol) and 2-bromoethyl chloroformate (3.49 g, 0.019 mol) in acetone (100 ml) over a period of 15 min. The reaction mixture was stirred for an additional 18 hr, filtered, and the filtrate evaporated to dryness in vacuo. The residue was taken up in chloroform (100 ml) and washed with water (3×20 ml). The chloroform layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to dryness. The residue was triturated with petroleum ether until a solid separated. The solid was filtered and recrystallized from ethanol (1.52 g, 43.0%). Mp was approximately 81-82° C. 1H NMR (CDCl3): δ 4.7 and 3.6 (4H, 2t, CH2CH2Br), 3.5, 3.3 and 3.1 (9H, 3s, 2CH3SO2 and NCH3).
Reaction SMILES: [OH-].[K+].O.[Br:4][C:5]1[N:25](S(C2C=CC=CC=2)(=O)=O)[C:8]2=[N:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)[N:12]=[C:7]2[CH:6]=1>C1COCC1>[Br:4][C:5]1[NH:25][C:8]2=[N:9][CH:10]=[C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=3)[N:12]=[C:7]2[CH:6]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
6.0 M Potassium hydroxide in water (0.50 mL, 3.0 mmol) was added to a solution of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (0.5 g, 0.9952 mmol) (from Example 1, Step 4) in THF (10 mL) and then the mixture was stirred at 70° C. for 3 hours. Most of the solvent was removed and the residue was treated with saturated ammonium chloride. The formed precipitate was filtered, washed with water, and dried to provide the desired product (0.34 g, 94%). LCMS calculated for C16H17BrN3O (M+H)+: m/z=362.0. Found 362.0.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[N+:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1

Procedure:
Under argon; to a solution of 3-iodonitrobenzene (3.00 g, 12.0 mmol) in pyridine (15 mL) were added ethyl 3-(4-hydroxyphenyl)propionate (2.81 g, 14.5 mmol), copper oxide (3.35 g, 42.2 mmol), and potassium carbonate (4.16 g, 30.1 mmol), and the resulting solution was heated to reflux for 40 hours. The reaction solution was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and once insoluble matter had been filtered off, and the filtrate was extracted with ethyl acetate out. The ethyl acetate layer was washed with 1 M hydrochloric acid, water and a saturated sodium bicarbonate solution, and then washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1→6:1), to thereby yield 1.12 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:11]1[C:15]([C:16](O)([CH3:18])[CH3:17])=[CH:14][N:13]=[CH:12]1.CS(Cl)(=O)=O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+].[Pd]>[CH3:1][C:2]1([CH3:20])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:11]1[C:15]([CH:16]([CH3:17])[CH3:18])=[CH:14][N:13]=[CH:12]1
Reactant: CC(C)(O)c1cncn1C1c2ccccc2CC1(C)C
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)c1cncn1C1c2ccccc2CC1(C)C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[3-(2,2-dimethyl-indan-1-yl)-3H-imidazol-4-yl]-propan-2-ol, which can be prepared as described in Example 22, (180 mg, 0.665 mmol) in pyridine (3 mL) is added 4-dimethylaminopyridine (50 mg, 0.4 mmol) and methanesulfonyl chloride (0.52 mL, 0.665 mmol). The reaction is permitted to stir for 90 minutes, at which time it is diluted with ethyl acetate and saturated aqueous NaHCO3. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is dissolved in ethanol (3 mL) and charged with 5% palladium on carbon (283 mg, 0.135 mmol). The reaction is placed under a hydrogen atmosphere (balloon pressure) for 1.5 hours, at which time it is filtered and the eluent concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:9) to provide 1-(2,2-dimethyl-indan-1-yl)-5-isopropyl-1H-imidazole. HRMS: (ESI) m/z 255.1870 [(M+H)+: Calcd for C17H23N2: 255.1861]; The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-(2,2-dimethyl-indan-1-yl)-5-isopropyl-1H-imidazole; 1H NMR (400 MHz, CD3OD) δ ppm 0.84 (s, 3 H), 1.33 (s, 3 H), 1.42 (d, J=6.6 Hz, 3 H), 1.49 (d, J=6.8 Hz, 3 H), 2.84-3.18 (m, 2 H), 3.23-3.32 (m, 1 H), 5.58 (s, 1 H), 7.24-7.48 (m, 4 H), 7.51 (s, 1 H), 8.19 (d, J=1.3 Hz, 1 H).
Reaction SMILES: Cl.[C:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]1)([O:4][CH3:5])=[O:3].C(N(CC)CC)C.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:2]([O:4][CH3:5])=[O:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)CC1CCCCN1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC1CCCCN1Cc1ccccc1
Reaction time: 5 h

Procedure:
In 13 ml of acetonitrile was dissolved 1.0 g (5.16 mol) of 2-carbomethoxymethylpiperidine hydrochloride, and 1.77 ml (12.72 mmol) of triethylamine and 0.76 ml (6.36 mmol) of benzyl bromide were added to the solution at room temperature, and the resulting mixture was reacted at the same temperature under stirring for 5 hours. After completion of the reaction, the obtained reaction mixture was filtered and then concentrated under reduced pressure, then, 25 ml of ethyl acetate and 15 ml of a saturated aqueous sodium hydrogen carbonate solution were added to the residue and the organic layer was extracted. The obtained organic layer was washed with 15 ml of a saturated aqueous sodium hydrogen carbonate solution, and saturated saline solution, dried over anhydrous magnesium sulfate, then, filtered and the filtrate was concentrated under reduced pressure to obtain 0.97 g of an oily substance. The resulting oily substance was purified by silica gel column chromatography (WAKOGEL C-200 (trade name), n-hexane/ethyl acetate=4/1(volume ratio)) to obtain 0.75 g (Isolated yield based on 2-carbomethoxymethylpiperidine hydrochloride=59%) of N-benzyl-2-carbomethoxymethylpiperidine.