Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1)=O.N1CCCCC1>CCO>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[O:17][C:16]([C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C=O)o2)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Yield: 91.4 %

Procedure:
A solution of oxindole (235 mg, 1.76 mmol), tert-butyl 3-(5-formylfuran-2-yl)phenylcarbamate (500 mg, 1.74 mmol) and piperidine (0.18 mL, 1.80 mmol) in EtOH (5.0 mL) was stirred at rt overnight. The resulting precipitate was collected by filtration to yield desired (E)-tert-butyl 3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenylcarbamate (640 mg). LCMS (ES): m/z 403 [M+1]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:35])([F:34])[C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][C:22](OCC)=[O:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[H-].O>CCOCC>[F:7][C:8]([F:34])([F:35])[C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH:19]([CH3:29])[C:20]([O:27][CH3:28])=[CH:21][CH2:22][OH:23])=[CH:16][CH:15]=2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a slurry of LiAlH4 (400 mg) in anhydrous ether (20 ml) is added dropwise at 0°, a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate (1.2 g) in ether (10 ml). After addition is complete, the reaction mixture is stirred for about 10 minutes. Excess hydride is decomposed with wet ether and water. After filtration, the filtrate is concentrated to give the alcohola, 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-penten-1-ol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:17]3[C:7]([CH2:8][C@@H:9]4[C@@H:14]([C:15]=3[CH:16]=1)[CH2:13][C@H:12]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:11][N:10]4[CH3:26])=[C:6](SC)[NH:5]2.[BH4-].[Na+].N>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:17]3[C:7]([CH2:8][C@@H:9]4[C@@H:14]([C:15]=3[CH:16]=1)[CH2:13][C@H:12]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:11][N:10]4[CH3:26])=[CH:6][NH:5]2
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4[nH]c(SC)c(c34)C[C@H]2N(C)C1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
Under argon, 10.74 g (23 mmol) of 3-(13-bromo-6-methyl-2-methylthio-8α-ergolinyl)-1,1-diethylurea is dissolved in 200 ml of trifluoroacetic acid. At a temperature of -15° C., sodium borohydride tablets are added thereto in 8 portions of 0.5 g each. After a reaction period of 11/2 hours at -15° C., the mixture is poured on 500 ml of ice, the solution is gently rendered alkaline with 25% strength ammonia solution, and extracted with methylene chloride. The organic phases are dried over magnesium sulfate and evaporated. The crude product is dissolved under argon in 100 ml of methanol p.a. and combined with 50 ml of 7N potassium hydroxide solution. The mixture is stirred for 2 hours at room temperature until the reaction is completed; then the mixture is poured on 150 ml of ice to work it up, and extracted with methylene chloride. The organic phases are washed with water and dried over magnesium sulfate. The concentrated crude product is chromatographed on 1.4 kg of silica gel with methylene chloride/methanol in a ratio of 97:3. In this way, 6.0 g is isolated which is crystallized from ethyl acetate/diisopropyl ether to complete the purification process, thus obtaining 5.44 g of 3-(13-bromo-6-methyl-8α-ergolinyl)-1,1-diethylurea (56% yield).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]2[CH2:37][OH:38])[CH:5]=1)(=[O:3])[NH2:2].Cl>O1CCOCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([C:8]3[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=[C:6]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH:25]4[CH2:37][OH:38])[N:7]=3)=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C(N)=O)nc(-c3ccc(Oc4ccc(F)cc4)cc3)n2)C(CO)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cc(N2CCNCC2CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 8 h
Yield: 28.9 %

Procedure:
To a solution of the tert-butyl 4-(6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (0.848 g, 1.62 mmol) in dioxane (25 mL) was added 4M HCl in dioxane (5 mL, 20 mmol). After stirring overnight the reaction was concentrated in vacuo. The residue was triturated with 10 mL acetonitrile, filtered, and rinsed with 10 mL acetonitrile. The solid was then successively suspended and filtered three times from warm acetonitrile. The solid residue was then partitioned between 10 mL EtOAc and 2 mL 2M aqueous Na2CO3 solution. The mixture was diluted with 50 mL EtOAc and 25 mL water, the organic layer was removed and the aqueous emulsion was washed once more with 50 mL EtOAc. The aqueous emulsion was filtered off and rinsed with water. The resulting pasty solid was triturated with 2 mL acetonitrile, filtered, rinsed once with 1 mL acetonitrile, and dried under vacuum to give 2-(4-(4-fluorophenoxy)phenyl)-6-(2-(hydroxymethyl)piperazin-1-yl)pyrimidine-4-carboxamide as a pale tan powder (0.198 g, 0.468 mmol, 29% yield). 1H NMR (400 MHz, DMSO-d6): 8.52 (2H, d, J=8.8 Hz), 8.32 (1H, s), 7.78 (1H, s), 7.31-7.24 (2H, m), 7.22-7.12 (3H, m), 7.04 (2H, d, J=8.8 Hz), 4.85 (1H, s), 4.79-4.60 (1H, very broad s), 3.83-3.74 (1H, m), 3.56 (1H, br s), 3.17-3.09 (1H, m), 3.05-2.94 (2H, m), 2.73-2.65 (1H, m), 2.63-2.54 (1H, m), 2.49-2.32 (2H, m). LC/MS: m/z=424.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:20])[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].[F:27][C:28]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O.O>C1COCC1>[F:27][C:28]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:16]1[CH:17]=[CH:18][N:19]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[C:15]1=[O:20]
Reactant: CS(=O)(=O)OCCCCOc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc[nH]c2=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccn(CCCCOc3cc(F)c(F)cc3F)c2=O)CC1
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-tert-butoxycarbonyl-1-piperazinyl)-2(1H)-pyrazinone (1.20 g, 4.30 mmol; from Example 48, Step 1) and t-BuOK (730 mg, 6.50 mmol) in THF (10 mL) was stirred for 10 min, and then added to a solution of methanesulfonic acid 4-(2,4,5-trifluoro-phenoxy)butyl ester (1.23 g, 4.3 nmol; from Step 2) in THF (50 mL). After being stirred at room temperature for 1 day, HPLC showed about 30% conversion. After 3 days, the reaction was worked up: water was added, THF was evaporated off and the aqueous mixture was extracted twice with EtOAc, dried and concentrated to yield 2.21 g of the crude product as a yellow oil. HPLC analysis showed a 5/1 ratio between the title product and the isomeric O-alkylated product.* Purification by chromatography on silica gel using EtOAc/hexane (1/2 to 1/1) as eluent gave 870 mg (42%) of the title product as a colorless oil. HPLC purity: 95%. MS m/z 483 (M+H)+. *Assignments were based on NMR analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH2:9][NH2:10])([CH3:8])[CH2:5][CH:4]([NH2:11])[CH2:3]1.[CH3:13][CH2:14][CH2:15][C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=O>CO>[CH2:22]([O:21][C:19]([CH:18]=[C:16]([NH:11][CH:4]1[CH2:3][C:2]([CH3:12])([CH3:1])[CH2:7][C:6]([CH:9]([NH:10][C:14]([CH2:15][CH2:16][CH3:18])=[CH2:13])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:8])[CH2:5]1)[CH2:15][CH2:14][CH3:13])=[O:20])[CH3:23]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Solvent: CO
Product: C=C(CCC)NC(C(=O)OCC)C1(C)CC(NC(=CC(=O)OCC)CCC)CC(C)(C)C1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To isophoronediamine (139.23 g, 0.819 mol) in methanol (700 ml) was slowly added with stirring ethyl butyroacetate (262.32 g, 1.660 mol) in methanol (700 ml) over 45 minutes, during which the temperature decreased slightly from 24° C. to 23° C. The reaction mixture was allowed to stand at 22° C. overnight (16 h). Further methanol was added, and removal of solvent and drying (91° C./100 Pa) gave 1-(1-ethoxycarbonyl-2-pent-1-enylamino)-3-(1-ethoxycarbonyl-2-pent-1-enylaminomethyl)-3,5,5-trimethylcyclohexane (EEMTCH formula shown below) as a clear light yellow pourable syrup (356.74 g, 97%), identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][CH2:21][N:20]([CH:25]5[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]5)[CH2:19][C:18]=4[C:17]([C:36]#[N:37])=[C:16]([Cl:38])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.O1CCOCC1>Cl>[ClH:38].[ClH:38].[ClH:38].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:15]=[C:16]([Cl:38])[C:17]([C:36]#[N:37])=[C:18]4[C:24]=3[O:23][CH2:22][CH2:21][N:20]([CH:25]3[CH2:28][NH:27][CH2:26]3)[CH2:19]4)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CN(C(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(C2CNC2)C3)c2ncnc(N)c12
Reaction time: 1 h

Procedure:
Tert-butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate (0.015 g, 0.0278 mmol) was dissolved in 4.0 M hydrogen chloride in dioxane (3.0 mL, 12 mmol) at room temperature and stirred for 1 hr and then concentrated in vacuo to give 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-azetidin-3-yl-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile trishydrochloride as a semi-solid. LCMS calculated for C21H24ClN8O (M+H)+: m/z=439.1; found: 439.1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCCC1.O>[OH:17][C:7]1([C:5]2[S:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: Cc1cc(C2(O)CCC3(CC2)OCCO3)sn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2(O)CCC(=O)CC2)sn1
Reaction time: 8 h

Procedure:
8-(3-Methyl-isothiazol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol (0.76 g, 0.0030 mol) was dissolved in tetrahydrofuran (10 mL), and a solution of 3.0 M of hydrogen chloride in water (5.0 mL) was added. The mixture was stirred overnight. Solid potassium carbonate was added to neutralize the acid and EtOAc was added to extract the product. The extract was dried and concentrated to give a crude product which was used directly for next step.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH2:20])=[O:19])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH2:20])=[O:19]
Reactant: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
190 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide was dissolved in methanol (6.9 mL), and 40 mg of 10% palladium carbon (50% water content) was added, followed by stifling for 1.5 hours under hydrogen atmosphere. The catalyst of the reaction mixture was filtered through celite, and the solvent was concentrated under reduced pressure and dried under vacuum to afford 126 mg of the title compound as a colorless solid (quantitative).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH2:12])=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[CH:10]=2)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: COc1cccc(OC)c1C=O
Reactant: Cn1nnc2cc(CN)ccc21
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)nnn2C

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.65 min.; [M+H]+: 381.09 g/mol.
Reaction SMILES: [C:1]1([C:7]2([C:26](OC)=[O:27])[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Li+].[BH4-]>C1COCC1.Cl>[OH:27][CH2:26][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]2[CH:23]3[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:25][CH:17]2[CH2:18]4)[CH2:22]3)=[O:14])[CH2:9][CH2:8]1
Reactant: COC(=O)C1(c2ccccc2)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC(CO)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 1.9 %

Procedure:
To a stirred solution of 1-(2-adamantyl) 4-methyl 4-phenylpiperidine-1,4-dicarboxylate (1.33 g, 3.35 mmol) and MeOH (0.068 mL, 1.67 mmol) in dry THF (20 mL) at rt was added solid LiBH4 (0.30 g, 13.4 mmol). The mixture was stirred at rt for 4 days. The mixture was diluted with 5% aq HCl (50 mL) and extracted with ether (175 mL). The organic layer was washed with satd aq NaHCO3 (50 mL), dried over MgSO4 and concentrated to afford crude title compound (1.21 g) as a white foam. A 40-mg portion was purified by prep HPLC to afford the title compound (23 mg) as a white solid. LC-MS Method 1 tR=2.12 min, m/z=370, 1H NMR (CDCl3) 1.58 (4H), 1.70-2.10 (12H), 2.23 (d, 2H), 3.13 (2H), 3.57 (s, 2H), 3.86 (m, 2H), 4.82 (s, 1H), 7.28 (1H), 7.38 (4H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[I:26]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.O>[C:1]1([S:7]([N:10]2[C:14]3[C:13](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:12]=[C:11]2[I:26])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
To a solution of 1-benzenesulfonyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine (1.0 g, 3.47 mmol) in THF (50 mL) cooled in a dry ice-acetone bath was added n-BuLi (2.1M in hexanes, 2.0 mL). The mixture was stirred for 20 minutes, warmed to 0° C. and stirred for an additional 30 minutes, then cooled to −78° C. A solution of iodine (1.06 g, 4.16 mmol) in THF (10 mL) was added dropwise over 5 minutes and the mixture was warmed to 0° C. and stirred for one hour. Water (10 mL) was added followed by 10% aq. Na2S2O3 (10 mL) and stirred for 5 minutes. Ethyl acetate (50 mL) was added and the organic phase was washed with water, saturated aqueous sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated to afford 1.0 g of 1-benzenesulfonyl-2-iodo-4-methoxy-7-azaindole as a yellow solid which was carried forward without further purification. MS m/z 415.
Reaction SMILES: [CH2:1]([C:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=[O:15])[NH:14][C:10]=2[C:9]([C:17]([F:20])([F:19])[F:18])=[CH:8][CH:7]=1)=[CH:4][CH3:5])[CH3:2].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=[O:15])[NH:14][C:10]=2[C:9]([C:17]([F:18])([F:20])[F:19])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: [H][H]
Reactant: CC=C(CC)c1ccc(C(F)(F)F)c2[nH]c(=O)n(C)c12
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC(CC)c1ccc(C(F)(F)F)c2[nH]c(=O)n(C)c12
Yield: 71.3 %

Procedure:
A mixture of 7-(1-ethylprop-1-en-1-yl)-1-methyl-4-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (486 mg, 1.71 mmol), 10% palladium on carbon (200 mg) and acetic acid (5 ml) was hydrogenated under 5 atom of hydrogen at 50° C. for 2 h. Catalyst was filtered off and filtrates were concentrated in vacuo. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by recrystallization from diisopropylether/n-hexane to give 350 mg (1.22 mmol, 72%) of the title compound as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:12](#[N:15])[CH:13]=[CH2:14].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:12]([CH:13]1[CH2:14][CH:17]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:15]
Reactant: CCOC(=O)CCl
Reactant: C=CC#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1C#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
40.2 g (291 mmol) of potassium carbonate were introduced into 89 ml of DMF at RT, 9.6 ml (146 mmol) of acrylonitrile, 15.5 ml (146 mmol) of ethyl chloroacetate and 1.96 g (8.61 mmol) of benzyltriethylammonium chloride were added, and the mixture was stirred at RT for 3 days. Water was added, the mixture was extracted with diethyl ether, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by vacuum distillation. 6.50 g (30% of theory) of the title compound (boiling range: 63-66° C./0.9 mbar) and 1.41 g (7%) of the corresponding cis-isomer (boiling range: 85-89° C./0.9 mbar) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].C([O:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](Cl)=[O:18])(=O)C.C(OC1C(=CC=CC=1)C(O)=O)(=O)C>CC(C)=O.N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:9])[C:3]=1[OH:10])[NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[OH:14]
Reactant: Nc1cc(Br)c(O)c(Br)c1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: CC(=O)Oc1ccccc1C(=O)O
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Br)c(O)c(Br)c1)c1ccccc1O
Yield: 78 %

Procedure:
2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. Then the solution was added by drops and with stirring to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetyl-salicylic acid (0.38 g.). The resulting solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate. The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3',5'-dibromo-2,4'-dihydroxybenzanilide (0.88 g.). Yield: 78%. The melting point of the compound is 182°-187° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[O:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].CC(C)=O>C(O)C.O.C(=O)([O-])[O-].[K+].[K+]>[OH:3][CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[O:5]1)[CH3:2]
Reactant: CC(=O)C1CCC=C(C)O1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: CC1=CCCC(C(C)O)O1
Reaction time: 0.5 h

Procedure:
A solution of 20.00 g of 16A in 40 ml of ethyl alcohol was added drop by drop to a solution of 2.71 g of sodium borohydride in 130 ml of ethyl alcohol and 65 ml of water, at 19°-23° C. After 30 minutes, 40 ml of acetone was added drop by drop. After 5 additional minutes, the reaction mixture was diluted with an equal volume of water, saturated with potassium carbonate, and extracted with ether. The extract was washed with saturated sodium chloride solution, dried (Na2SO4) and stripped of solvent. Some water remained in the residue. 100 ml of acetone was added to the residue; the solution was dried (Na2SO4) and stripped of solvent to give 2-(1-hydroxyethyl)-3,4-dihydro-6-methyl-2H-pyran (16B), as a liquid, b.p.: not determined.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][N:14](CC4C=CC=CC=4)[CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[CH2:9]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(OCC2CC3CN(Cc4ccccc4)CCN3C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of 1.20 g (3.53 mmol) of (7SR,8aSR)-7-(4-fluorophenoxy)methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 2), 30 mL of methanol and 2.5 mL of 5.0M ammonium formate was treated with an aqueous slurry of 0.15 g of 10% palladium on carbon. The mixture was heated at reflux for 48 h, cooled to ambient temperature, filtered through Celite, and the filtrate was evaporated. The residue was taken up in dilute aqueous ammonium hydroxide and extracted with chloroform (3×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated to give 0.874 g (99%) of the title compound. 13C NMR (CDCl3): δ 32.0, 34.5, 45.2, 50.9, 53.4, 57.0, 63.7, 72.6, 115.4, 115.5, 115.8, 155.1, 155.6, 158.7. HRMS calcd for C14H20FN2O (MH+): 251.156, found: 251.155.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[N:29]([CH:46]([CH3:48])[CH3:47])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:49])[N:29]([CH:46]([CH3:47])[CH3:48])[CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1
Reactant: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 67.7 %

Procedure:
A solution of 3-t-butyldiphenylsilyloxy-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (945 mg, 1.38 mmol) (obtained as described in Reference Example 60(2)) in anhydrous tetrahydrofuran (50 ml) were added successively acetic acid (0.10 ml, 1.66 mmol) and a 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1.66 ml, 1.66 mmol) in an ice bath, and the mixture was stirred in the ice bath for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate ethyl acetate:methanol (10:1) as the eluant to afford 3-hydroxy-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)-ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (433 mg, yield 66%) as a white solid.