Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[F:3][CH:4]([F:32])[O:5][C:6]1[C:11]2[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C:10]=2[C:9]([C:22]2[O:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=2)=[CH:8][CH:7]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]3[C:6]([O:5][CH:4]([F:3])[F:32])=[CH:7][CH:8]=[C:9]([C:22]4[O:23][CH:24]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:26]=4)[C:10]=3[C:14]=2[CH:15]=1
Reactant: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc([N+](=O)[O-])cc4c23)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(N)cc4c23)n1
Yield: 87.5 %

Procedure:
A mixture of methanol (100 mL) and ethyl acetate (100 mL) was added to the ethyl 2-(4-(difluoromethoxy)-8-nitrodibenzo[b,d]furan-1-yl)1,3-oxazole-4-carboxylate (0.8 g, 1.91 mmol) from step 7 of example 47. To the reaction mixture, palladium-carbon (0.30 g) was added. The reaction mixture was transferred to the hydrogenation flask and hydrogenation was performed at room temperature (40 psi-hydrogen) for 2 hours. The reaction mixture was filtered through celite. The filtrate was evaporated at reduced pressure to give the desired product. Yield—87.5%. Rf—0.5 (Ethyl acetate:Hexane (1:1)
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[O:13]=[C:14]1[NH:18][C:17](=[O:19])[O:16][N:15]1[CH2:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH2:26][C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.[CH2:44]([O:46][CH2:47][CH2:48][NH2:49])[CH3:45].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:13]=[C:14]1[NH:18][C:17](=[O:19])[O:16][N:15]1[CH2:20][C:21]1[CH:43]=[CH:42][C:24]([O:25][CH2:26][C:27]2[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([NH:49][CH2:48][CH2:47][O:46][CH2:44][CH3:45])=[O:41])=[CH:35][CH:34]=3)[CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: CCOCCN
Reactant: O=C(O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1ccc(-c2cccc(COc3ccc(Cn4oc(=O)[nH]c4=O)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
WSC hydrochloride (163 mg) was added to a mixture of 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-4-biphenylcarboxylic acid (293 mg), (2-ethoxyethyl)amine (0.11 ml), HOBt (142 mg) and DMF (10 ml), followed by stirring at room temperature for 27 hours. The solvent was evaporated under a reduced pressure, and chloroform/methanol (4/1) was added to the residue, followed by washing with water and a saturated ammonium chloride aqueous solution. The solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol), the resulting foamy substance was further crystallized by adding diethyl ether, and the resulting crystals were recrystallized from methanol to obtain 3′-({4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-N-(2-ethoxyethyl)-4-biphenylcarboxamide (135 mg) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[C:4]([NH:10][C@H:11]([C@@H:34]([OH:36])[CH3:35])[C:12]([NH:14][NH:15][C:16](=[O:33])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CN(C=O)C.N1C=CN=C1.[C:48]([Si:52](Cl)([CH3:54])[CH3:53])([CH3:51])([CH3:50])[CH3:49]>CCOC(C)=O.O>[Si:52]([O:36][C@@H:34]([CH3:35])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[CH3:37])[C:12]([NH:14][NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:13])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(COc2ccc(C(=O)NNC(=O)[C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)cc2)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(C(=O)NNC(=O)[C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 107.3 %

Procedure:
A 100 mL round bottomed flask was charged with N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-4-(4-methoxybenzyloxy)benzohydrazide (3.53 g, 6.7 mmol) and DMF (120 mL). Imidazole (1.84 g, 27 mmol) and tert-butyldimethyl silyl chloride (2.52 g, 16.75 mmol) were then added to the mixture which was stirred at room temperature for 17.5 h. Water (60 mL) was added to the mixture followed by EtOAc (100 mL). The phases were partitioned and the organic phase washed with water (70 mL) (×4), brine (50 mL), dried (Na2SO4) and concentrated to furnish a white solid. Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a colorless oil (4.58 g, 35% yield). No 1H data available.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C1(O)CCCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2cc(Br)cc(Cl)c2N1
Reactant: CC(=O)NN
Solvent: OC1CCCCC1
Product: Cc1nnc2n1-c1c(Cl)cc(Br)cc1CC2
Temperature: 100 °C

Procedure:
To a solution of 6-bromo-8-chloro-3,4-dihydroquinoline-2(1H)-thione (80-2; 0.45 g, 0.0016 mol) in cyclohexanol (20 mL) was added acetic hydrazide (0.241 g, 0.0032 mol) and the reaction mixture was heated at 100° C. for 1 h under microwave irradiation conditions. Then 1.5 g of molecular sieves powder was added and the reaction mixture was again heated at 190° C. for 2 h under microwave conditions. The reaction mixture was filtered and the filtrate was evaporated. The crude was purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ: 7.85 (s, 1H), 7.76 (s, 1H), 2.87 (bs, 4H), 2.50 (s, 3H). MS (M+1): 298.2.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH2:32][CH2:33][CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in CH2Cl2 (5 ml) are slowly added triethylamine (0.36 mmol) and 1-butanesulfonyl chloride (0.36 mmol) at 0° C. The reaction mixture is stirred at room temperature for 15 h. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of CH2Cl2. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product. Purification of the residue by silica gel column chromatography affords title compound in 39% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 4-chlorosalicylic acid (75 g, 435.6 mmol) in anhydrous DMF (871 mL) was added Cs2CO3 (70.7 g, 217.8 mmol) and MeI (27.5 mL, 439.9 mmol) sequentially. The reaction mixture was stirred at room temperature overnight. Ice cold water (3 L) was added to the reaction mixture and the precipitated solid was filtered and dried to provide VII-1-I (75 g, 92% yield).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC1C=CC=CC=1)C1OC1.[Cl-].[Li+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].O1CCCC1.C(O)(=O)C>[CH2:6]([O:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccccc1
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC(CCl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Epichlorohydrin is reacted with benzyl alcohol in the presence of tetrabutylammonium bisulfate in aqueous sodium hydroxide, at room temperature. The product of this reaction, benzyl glycidyl ether, is isolated by conventional means and is then added slowly to a suspension of lithium chloride in tetrahydrofuran and acetic acid, at 40°-70° C., preferably below 60° C. The reaction mixture is allowed to cool to room temperature, and stirred for 2-10 hours, preferably 3-6 hours. The product is isolated by extraction, washed and dried to provide 1-benzyloxy-3-chloro-2-propanol. To this product is then added methoxymethyl propionate, which is prepared by adding propionic anhydride to dimethoxymethane in the presence of an ion exchange resin, e.g., Amberlyst 15, maintaining the temperature between 40°-60° C., preferably between 40°-50° C. during the addition. The reaction mixture is aged and cooled, then filtered, washed and distilled. This product, methoxymethyl propionate, is reacted with 1-benzyloxy-3-chloro-2-propanol in an aprotic solvent, e.g., hexanes, in the presence of p-toluenesulfonic acid hydrate at reflux. Distillation and washing affords the product 1-benzyloxy-3-chloro-2-(propionyloxy)methoxypropane. Finally, to prepare the compounds of Formula (III), 1-benzyloxy-3-chloro-2-(propionyloxy)methoxypropane, is refluxed with an alkali metal alkanoate, e.g., sodium propionate, in an aprotic solvent, e.g., toluene, after which a phase transfer catalyst such as tetrabutylphosphonium chloride is added. The reaction mixture is stirred at 90° C. to reflux temperature for 1-3 days, preferably 2 days, at which time more tetrabutylphosphonium chloride and solvent may be added, if required. The mixture is heated to reflux and the distillate removed, then stirred at 90° C. to reflux temperature for 3-16 hours, preferably 5-10 hours, then cooled to ambient temperature. The mixture is then washed with water and brine, and the organic phase is separated and concentrated to yield 1-benzyloxy-3-propionyloxy-2-(propionyloxy)methoxy propane. In an analogous manner, other glycerol derivatives of Formula (III) may be prepared.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[O:2]>C(O)C.[Pd]>[CH:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:2]
Reactant: C=CCCCCCCCCCNC=O
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCNC=O
Reaction time: 10 h
Yield: 99.2 %

Procedure:
N-formyl-1-aminoundec-10-ene (467 mg) was dissolved in ethanol (2 ml). Pd/C (46 mg) was added and the mixture submitted to hydrogenation at atmospheric pressure during 10 h. The reaction mixture was filtered through a short column of celite and the solvent evaporated under vacuo. This yielded N-formyl-1-aminoundecane (468 mg, yield: 100%) as a white solid
Reaction SMILES: [BH4-].[Na+].[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[C:32](=[O:34])[CH3:33])[CH2:23]1)[C@@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6].C(O)(=O)C.C(Cl)(Cl)Cl>C(O)C>[S:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C@H:22]1[CH2:41][CH2:40][C@@:39]2([CH3:42])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:38]2[CH2:37][CH2:36][C@@:35]2([CH3:43])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[CH:32]([OH:34])[CH3:33])[CH2:23]1)[C@H:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]1[OH:6]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium borohydride (60 mg) was added to a solution of 6-(pregn-5-en-20-one-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside (250 mg) in absolute ethanol (7 ml). After stirring at room temperature for 4 hours, the solution was cooled and glacial acetic acid (10 ml) was slowly added. The solution was added to chloroform (100 ml) and successively washed with water (3 ×), 1N sodium bicarbonate (2 ×), and water (1 ×) and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the product as a fine white solid. The 200 MHz NMR spectrum of the peracetylated derivative was in accord with the desired structure. TLC data and Rf values are given in the above Table.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)NC(=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)NC(=O)C2
Yield: 1.9 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(2-oxoindolin-6-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.066 g; 0.159 mmol), sodium hydroxide 10N (0.159 mL; 1.59 mmol) in methanol (1.5 mL). Purification by preparative HPLC (HPLC method 2) furnished 0.0012 g (2%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([OH:32])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:36][C@H:37]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=[O:35])C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9]([O:32][C:33]([O:36][CH3:37])=[O:35])[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][CH2:20][O:21]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2OC12
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCCO4)CC[C@H]3[C@H]12
Yield: 74.9 %

Procedure:
The procedure of Example 12 was repeated except that 44.6 mg (0.1 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2 -epoxy-7α-hydroxypregn-5-en-3β-yl acetate was used in lieu of 49.0 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregn-5-en-3β-yl acetate to give 37.8 mg of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate (yield: 75%)
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]=[CH:10][C:11](=[CH2:13])[CH3:12].O>CCCCCC>[CH3:12][C:11]1[CH2:13][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][CH2:9][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: C=CC(=C)C
Solvent: CCCCCC
Solvent: O
Product: CC1=CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Bis-trifluoromethanesulphonimide (70, 5 mg, 0.25 mmol) was stirred in hexane (4 ml) at room temperature. Benzaldehyde (510 μl, 5.0 mmol) and isoprene (750 μl, 7.5 mmol) were added and the mixture stirred at room temperature overnight. Water (5 ml) was added and the aqueous layer was extracted with hexane (3×3 ml). The combined organic layers were filtered through celite and analysed by glc. A yield of 42% of 4-methyl-6-phenyl-5,6-dihydropyran was observed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH:22]([O:24]C)[OH:23])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.CC(=CC)C.FC(F)(F)C(O)=O.Cl([O-])=O.[Na+].O.P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC(O)C[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 229.1 %

Procedure:
To a stirred mixture of 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol (Example 5a, 90 mg, 0.25 mmol), 2-methylbut-2-ene (2 M in THF, 1 mL), tert-butanol (0.5 mL) and trifluoroacetic acid (0.03 mL, 0.4 mmol) was added a solution of sodium chlorite (80%, 70 mg, 0.62 mmol) and sodium dihydrogenphosphate monohydrate (80 mg, 0.58 mmol) in water (0.6 mL) at 0° C. The reaction mixture was then stirred at RT for 1.5 hr. The aqueous layer was separated, extracted with THF (1.5 mL), neutralized with solid sodium bicarbonate to pH=6, and extracted with THF (2×1 mL). The combined organic solutions were dried (Na2SO4) and concentrated to give 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)acetic acid (195 mg) which was used in the next step without further purification. MS found: (M+H)+=341.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C([Li])CCC.[CH:17](=[N:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>C(OCC)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([C@@H:17]([NH:21][S@:22]([C:24]([CH3:25])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][CH:5]=1
Reactant: CCCC=N[S@@](=O)C(C)(C)C
Reactant: FC(F)(F)c1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCC[C@H](N[S@@](=O)C(C)(C)C)c1cccc(C(F)(F)F)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
To a solution of 2-bromo-6-trifluoromethyl-pyridine (480 mg, 2.2 mmol) in anhydrous diethyl ether (20 mL) at −78° C. is added n-butyllithium (1.6 M in hexanes, 1.5 mL, 2.4 mmol) dropwise over 20 min. After stirring at −78° C. for 30 min, (S)-2-methyl-propane-2-sulfinic acid butylideneamide is added. The resultant mixture is stirred at −78° C. for 30 min and is then allowed to warm gradually to room temperature overnight. The reaction mixture is poured into saturated aqueous ammonium chloride solution (30 mL) and extracted with EtOAc (3×30 mL). The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo to afford (S,S)-2-methyl-propane-2-sulfinic acid 1-(6-trifluoromethyl-pyridin-2-yl)-butylamide as a yellow oil (290 mg, 42%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][N:5]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:9]([F:8])[CH:10]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(C=O)cc1F
Solvent: Cc1ccccc1
Product: COc1ccc(C=NCC(OC)OC)cc1F

Procedure:
2,2-Dimethoxyethylamine (13.85 ml, 0.13 mol) is added to a solution of 3-fluoro-4-methoxybenzaldehyde (20 g, 0.13 mol) in toluene (200 ml). The resulting solution is flushed with nitrogen gas and then heated overnight under reflux in a Dean-Stark apparatus. The solvent is then removed under reduced pressure to yield (2,2-dimethoxy-ethyl)-[1-(3-fluoro-4-methoxy-phenyl)-methylidene]-amine. This intermediate (31 g, 0.13 mol) is dissolved in ethylacetate and acetic anhydride (13.1 g, 0.13 mol) added. Platinum oxide (0.3 g) is then added, under a blanket of nitrogen, and the resulting mixture is stirred under a hydrogen atmosphere until uptake is complete. Filtration, washing with saturated aqueous NaHCO3 (3×100 ml), brine and water, drying over MgSO4 and concentration then gives N-(2,2-dimethoxy-ethyl)-N-(3-fluoro-4-methoxy-benzyl)-acetamide. This intermediate (38.9 g, ca 0.13 mol) is dissolved in anhydrous CH2Cl2 and then added slowly over 20 mins to a stirred mixture of AlCl3 (90 g) and CH2Cl2 under an atmosphere of nitrogen. The total volume of CH2Cl2 is 250 ml. The mixture is stirred for a further 10 mins at room temperature and is then cooled with an ice bath during the addition of aqueous 40% NaOH. The mixture is further diluted with water (250 ml), filtered through glass wool, the organic phase separated and the aqueous phase further extracted with CH2Cl2 (2×200 ml). Drying over MgSO4 and evaporation under reduced pressure yields a crude oil which is purified by flash silica chromatography (eluant: 1% methanol in CH2Cl2) to give as one of the products 1-(7-fluoro-6-methoxy-1H-isoquinolin-2-yl)-ethanone. This intermediate (0.60 g, 2.7 mmol) is mixed with glyoxylic acid (0.325 g, 3.5 mmol) and water (10 ml) and the resulting mixture is stirred at room temperature for 20 min. Concentrated hydrochloric acid (10 ml) is then added and the mixture heated to reflux for 1 h. Concentration and purification by preparative HPLC gives (7-fluoro-6-methoxy-isoquinolin-4-yll)-acetic acid, [MH]+ 236.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17]C(=O)OC(C)(C)C)[CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[ClH:26]>C(OCC)(=O)C>[ClH:26].[ClH:26].[NH2:17][C@H:14]1[CH2:15][CH2:16][N:12]([C:9]2[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:25])[CH3:1])(=[O:4])=[O:5])=[CH:11][CH:10]=2)[CH2:13]1
Reactant: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(N2CC[C@H](N)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In ethyl acetate was dissolved 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate, 200 ml of a solution of 4M hydrochloric acid in ethyl acetate was added thereto, and the mixture was stirred at room temperature for 3 days. The solvent was evaporated, and then, diethyl ether was added to the residue, and the precipitates were collected by filtration to obtain 4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide dihydrochloride. To the 4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide dihydrochloride were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated under reduced pressure to obtain 5.85 g of 4-[(S)-3-aminopyrrolidin-1-yl]-N,N-dimethyl-benzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[C:4]([CH3:12])[N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)c(N)cc1Cl
Reaction time: 20 h
Yield: 88.1 %

Procedure:
A mixture of the nitropyridine 46 (1.48 g, 7.85 mmol), MeOH (50 mL), and 5% Pd-C (150 mg) was shaken under H2 (20-30 psi) for 20 h. The mixture was filtered and the filtrate was rota-evaporated to dryness to give 1.09 g (87%) of the diamine 47 as a brown powder, mp 128°-130° C. 1H NMR (CDCl3) δ1.661 (s, 3H), 3.233 (bs, 2H), 4.183 (bs, 2H), 6.880 (s, 1H).