Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([N:45]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCc3ccccc3)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(Cc3ccccc3)C(=O)C(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (3S,5R)-3-Benzylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (68.5 mg, 0.098 mmol) in CH2Cl2 is treated with i-Pr2NEt (40.2 μL, 0.235 mmol) and pivaloylchloride (23.9 μL, 0.196 mmol). The solution is stirred at room temperature for 18 h. Additional i-Pr2NEt (20 μL, 0.12 mmol) and pivaloylchloride (12 μL, 0.095 mmol) are added and stirring is continued for 9 h. The reaction mixture is partitioned between EtOAc and 1 M NaHCO3, the organic layer is washed with 1 M NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in THF/piperidine (5:1) (6 mL), the solution is stirred at room temperature for 2.5 h and then concentrated in vacuo. The crude product is purified by RP-HPLC to afford the title compound. MS: 559 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.40 min.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10]COS(C)(=O)=O)=O)(C)(C)C.[F:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[C:32]1[C:33](=[O:52])[NH:34][C:35](=[O:51])[N:36]([CH2:39][C:40]2[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=2[F:50])[C:37]=1[CH3:38].C(=O)([O-])[O-].[K+].[K+].[C:59]([O:62][CH:63]([CH3:65])[CH3:64])(=[O:61])[CH3:60]>O.CN(C=O)C>[NH2:8][C@H:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:10][N:34]1[C:33](=[O:52])[C:32]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:24]=2[F:23])=[C:37]([CH3:38])[N:36]([CH2:39][C:40]2[C:45]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=2[F:50])[C:35]1=[O:51].[C:59]([O:62][CH:63]([CH3:65])[CH3:64])(=[O:61])[CH3:60]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)[nH]c2=O)c1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOS(C)(=O)=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Temperature: 55 °C

Procedure:
Methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester 1d (19.7 kg), 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (16.5 kg), potassium carbonate (powder, 325 mesh, 13.4 kg) and DMF (101 L) were charged to a reactor. The mixture was stirred at 55° C. After reaction completion, the reactor was cooled to 20° C. and isopropyl acetate (132 L) was charged, followed by water (157 L). After agitation and settling, the layers were separated and the organic layer washed with water (87 L). After agitation and settling, the water layer was removed. To the organic layer was charged methanesulfonic acid (11.2 kg) and the reactor contents were heated to 60° C. for 1-2 hours. The reactor contents were cooled to 20° C. and a solution of potassium carbonate/water (26.8 kg/140 L) was added slowly, agitated, and then allowed to settle prior to separation of layers. The organic layer was treated with a solution of 85% phosphoric acid/H2O (22.6 kg/236 kg). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous layer was washed with isopropyl acetate (2×167 kg) and the layers were separated. A solution of potassium carbonate/water (36.1 kg/139 kg) was added slowly to the aqueous layer. Isopropyl acetate (206 kg) was charged; the mixture was agitated and then allowed to settle. The aqueous layer was removed and the organic layer was concentrated to provide a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in isopropyl acetate (125.4 kg, 30.7 kg contained, 86% yield) for use in the next step. LCMS (ESI) m/z 546.2 (MH+)
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[ClH:21].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][Cl:26]>CN(C=O)C>[ClH:26].[ClH:21].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[CH:11]1
Reactant: CN(C)CCCl
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ncccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(S(=O)(=O)c2ccccc2)c2cccnc21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.55 mmol) in dry DMF is chilled to 0° C., treated with sodium hydride (60% in oil, 97 mg, 2.43 mmol), stirred for 3 h at 20° C., cooled to −20° C., treated with 2-(dimethylamino)-ethyl chloride hydrochloride (336 mg, 2.33 mmol), stirred at 60° C. for 16 h, cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the free amine of the title compound as a yellowish gum. The gum is dissolved in ethanol, treated with 1N aqueous HCl and concentrated in vacuo. Crystallization of the resultant residue from ethanol/ether affords the title compound as a light tan solid, 111 mg, mp 214–217° C., characterized by mass spectral and HNMR analyses.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]4[O:21][CH2:20][O:19][C:14]=4[CH:15]=3)[C:10]2=[O:22])[CH2:2]1.[Br:23][CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>>[BrH:23].[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][CH2:24][N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]4[O:21][CH2:20][O:19][C:14]=4[CH:15]=3)[C:10]2=[O:22])[CH2:2]1
Reactant: BrCCc1ccc2ccccc2c1
Reactant: O=C1c2cc3c(cc2CCN1CC1CCCCNC1)OCO3
Product: Br
Product: O=C1c2cc3c(cc2CCN1CC1CCCCN(CCc2ccc4ccccc4c2)C1)OCO3

Procedure:
Prepared from 2-[(hexahydro-azepin-3-yl)-methyl]-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 2-(2-bromo-ethyl)-naphthalene analogously to Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]4[O:22][CH2:21][O:20][C:18]4=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][Cl:33])=[CH:27][CH:26]=1>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[ClH:33].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[C:14](=[O:15])[CH2:13][C:12]4[CH:16]=[C:17]5[O:22][CH2:21][O:20][C:18]5=[CH:19][C:11]=4[CH2:10][CH2:9]3)[CH2:2]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: O=C1Cc2cc3c(cc2CCN1CC1CCCNC1)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCN2CCCC(CN3CCc4cc5c(cc4CC3=O)OCO5)C2)cc1
Product: Cl

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 2-(4-methoxyphenyl)-ethylchloride in dimethyl-formamide/potassium carbonate at 120° C. analogously to Example 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=CC=1.ICC.N1CCOCC1>CN(C)C=O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH3:2])[CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 34: (+)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.40 g, 1.38 mmol), dimethyl formamide (3 mL), iodoethane (1.1 mL, 13.8 mmol) and morpholine (2 mL). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 45:55). Yield: 0.11 g. [α]D=+19.8° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 118-120° C.; MS m/z (relative intensity, 70 eV) 228 (M+, 14), 141, (16), 127 (14), 72 (26), 71 (bp).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.O.[OH-].[Na+:24]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:14]([C:18]([O-:20])=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.[Na+:24]
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccncc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])c1cccc2c1CCN(Cc1ccncc1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.6 %

Procedure:
Methyl 2-(pyridine-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (1.14 g, 4.04 mmol) was dissolved in dioxane (15 mL) and water (5 mL) then added a solution of 2N aqueous sodium hydroxide (2.22 mL, 4.45 mmol). The reaction mixture was stirred at room temperature for 2 days then concentrated under vacuum. The remaining oil was azeotroped with toluene and dried under high vacuum to afford 1.25 g of sodium 2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate as a pale yellow oil/foam. MS (ESI, pos. ion) m/z: 269.0 (M+1).
Reaction SMILES: [Mg].BrCCBr.Cl[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1.O>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)([OH:28])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: OC1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium metal (4.15 g, 170.5 mmol) in anhydrous THF (40 ml) is added 1,2-dibromoethane (1.53 g, 8.12 mmol) and the mixture warmed gently. To the reaction mixture is added a solution of 1-chloromethyl-4-fluoro-benzene (23.5 g, 162.4 mmol) in THF (20 ml) dropwise over 1.5 hours. The reaction mixture is cooled to RT and stirred for 0.5 hours followed by cooling to −10° C. and addition of a solution of 1-benzyl-piperidin-4-one (9.19 g, 48.6 mmol) in THF (20 ml) dropwise over 0.5 hours. During the addition the reaction temperature is maintained below 0° C. After addition is complete the reaction is allowed to reach RT and stirred for 4 days. The resultant suspension is cooled in ice, treated with saturated ammonium chloride, stirred for 0.3 hours, treated with water and the mixture extracted with ethyl acetate. The ethyl acetate is dried with magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (methanol:dichloromethane: anmuoniumhydroxide, 1:100:0.5 elution) to afford 1-benzyl-4-(4-fluoro-benzyl)-piperidin-4-ol [MH]+ 300.8
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[NH:1]([C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccccc2)sc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Nc1ccccc1
Reaction time: 19 h

Procedure:
A vial was charged with copper acetate (77 mg, 0.425 mmol), ethyl 2-amino-5-phenylthiophene-3-carboxylate (100 mg, 0.404 mmol), phenylboronic acid (99 mg, 0.809 mmol), dichloromethane (2 ml), and triethylamine (0.113 ml, 0.809 mmol). The blue-green reaction mixture was magnetically stirred for 19 hours and then concentrated to a volume of 0.5 mL. The crude reaction mixture was purified by silica gel chromatography (7-60% dichloromethane/hexanes) to afford ethyl 2-anilino-5-phenylthiophene-3-carboxylate.
Reaction SMILES: [OH:1][C:2]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=O.Cl(O)(=O)(=O)=O.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCc1c(C)cc(OC)c(OC)c1O

Procedure:
To a solution (15 ml) of 3 g of methyl 21-(2-hydroxy-3,4-dimethoxy-6-methylbenzoyl)heneicosanoate in ethyl acetate are added 0.015 ml of 60% perchloric acid and 600 mg of 5% palladium-on-carbon, and catalytic reduction is carried out at a 70° C. using hydrogen gas at the pressure of 100 kg/cm2. The catalyst is filtered off and the filtrate is washed in sequence with ice water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure gives colorless crystals of methyl 22-(2-hydroxy-3,4-dimethoxy-6-methylphenyl)docosanoate. m.p. 71°-72.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19]([NH:21][CH2:22][CH2:23][OH:24])[CH3:20]>C(Cl)Cl>[CH2:19]([N:21]([CH2:22][CH2:23][OH:24])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Benzylchloroformate (5.91 g, 34.67 mmol) and triethylamine (5.2 ml) were added sequentially to a solution of 2-(ethylamino)ethanol (3.0 g, 33.66 mmol) in DCM (180 ml) at 0° C. The ice bath was removed and the reaction mixture was allowed to stir overnight at ambient temperature. The solution was washed with 10% citric acid (100 ml) and H2O (2×100 ml) and concentrated in vacuo. The organic phase was dried (MgSO4), concentrated under reduced pressure, and the concentrate was purified by column chromatography (ISCO, silica gel column, eluting with 60→100% EtOAc/hexanes for 14 minutes) to give the title compound (7.29 g, yield: 97%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.C1([O:18][C:19](=O)[NH:20][C:21]2[C:30]3[CH2:29][CH:28]([OH:31])[CH2:27][CH2:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)C=CC=CC=1.O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][C:19]([NH:20][C:21]2[C:30]3[CH2:29][CH:28]([OH:31])[CH2:27][CH2:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: NCCOc1ccc(F)cc1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=C(NCCOc1ccc(F)cc1)Nc1cccc2c1CC(O)CC2
Reaction time: 0.67 h
Yield: 89.2 %

Procedure:
To 2-(4-Fluorophenoxy)ethylamine (27.4 mg, 0.18 mmol) was added a solution of (7-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-carbamic acid phenyl ester (50.0 mg, 0.18 mmol) in 1.5 mL dimethylsulfoxide. The mixture was stirred for 40 minutes, and then poured into water. The resulting solid was filtered and dried under reduced pressure (54.2 mg, 89.2% yield).
Reaction SMILES: [F:1][CH2:2][C@@:3]12[C:32]3[CH:33]=[C:34]([N+:37]([O-])=O)[CH:35]=[CH:36][C:31]=3[O:30][CH2:29][CH2:28][C@@H:4]1[S:5](=[O:27])(=[O:26])[C:6]([CH3:25])([CH3:24])[C:7]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8]2>CCOC(C)=O.CCO.[Pd]>[F:1][CH2:2][C@@:3]12[C:32]3[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:31]=3[O:30][CH2:29][CH2:28][C@@H:4]1[S:5](=[O:26])(=[O:27])[C:6]([CH3:24])([CH3:25])[C:7]([N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:8]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc([N+](=O)[O-])ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc(N)ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Yield: 100.2 %

Procedure:
A solution of tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (647 mg, 1.13 mmol) in EtOAc (15 mL) and EtOH (5 mL) was hydrogenated at 1 atm. in the presence of palladium (10% wt. on activated carbon) (120 mg, 1.13 mmol) for 5 h at RT. The mixture was filtered through the pad of celite and washed 3 times with EtOAc. The filtrate was concentrated in vacuo to give tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-amino-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (613 mg, 100%) as a white solid. LC/MS (ESI+) m/z=564 (M+Na).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[CH2:35]([O:42][C:43]([NH:45][C@H:46]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:47](O)=[O:48])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[CH2:35]([O:42][C:43]([NH:45][C@H:46]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:47]([O:9][C@@H:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)=[O:48])=[O:44])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.4 %

Procedure:
(R)-quinuclidin-3-ol (214 mg, 1.68 mmol), N,N′-methanediylidenedicyclohexanamine (347 mg, 1.68 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (227 mg, 1.68 mmol) were added to a solution of (R)-2-(benzyloxycarbonylamino)-2-phenylacetic acid (400 mg, 1.40 mmol) in THF (15 ml). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. DCM was added, and the insoluble solid was removed by filtration. The organic phase was washed twice with Na2CO3 and brine, dried over Na2SO4 and evaporated. The crude was purified by silica gel flash chromatography (DCM/MeOH=9/1) to obtain (R)—((R)-quinuclidin-3-yl) 2-(benzyloxycarbonylamino)-2-phenylacetate (63 mg; 11.4% yield). ((R)-quinuclidin-3-yl 2-(benzyloxycarbonylamino)-2-phenylacetate is also collected (300 mg; 54.2% yield)).
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:12]=O.[OH-].[Na+]>O1CCOCC1>[N+:1]([C:4]([CH3:12])([CH3:6])[CH2:5][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)([O-:3])=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=O
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(CN1CCCC1)[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h

Procedure:
18 ml of 2-nitropropane and 16.5 ml of pyrrolidine were dissolved in 60 ml of dioxan. 15 ml of aqueous formaldehyde solution (37%) and 8 ml of 2% sodium hydroxide solution were added at 5° C. The mixture was heated to 90° C. while stirring for 1 hour, cooled and thereafter extracted with 3×150 ml of ethyl acetate. Upon distillation in a water-jet vacuum, we obtained 19 g of 1-(2-nitro-2-methylpropyl)-pyrrolidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](I)[CH3:31].O>CN(C=O)C.C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH:15]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)[CH2:30][CH3:31])=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCOC(=O)c1ccc(NCc2nccnc2OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(CC)c2nccnc2OCc2ccccc2)cc1
Reaction time: 36 h

Procedure:
Ethyl 4-(2-benzyloxypyrazin-3-ylmethylamino)benzoate (455 mg) was dissolved in dry DMF (4 mL) and added to a suspension of sodium hydride (51 mg of a 60% dispersion in mineral oil) in DMF (4 mL) precooled to 0° C. under argon dropwise over fifteen minutes. After stirring for thirty minutes at 0° C. ethyl iodide (0.12 mL) was added and the mixture stirred for 36 hours. The solution was poured into water (50 mL) and the mixture made acidic with glacial acetic acid. The organic phase was then extracted with ethyl acetate (3×50 mL), washed with water (50 mL) and brine (50 mL) and dried (MgSO4). After removal of the solvent, the residue was purified by MPLC (eluting 20% ethyl acetate in hexane, silica) to give ethyl 4-(1-(2-benzyloxypyrazin-3-yl)prop-1-ylamino)benzoate as an oil which was used in the next step without further purification, (260 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1(C)C=CC=CC=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[S:16]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[N:4][CH:3]=2)=[CH:17]1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Brc1cncc(-c2ccsc2)c1
Temperature: 75 °C
Yield: 337.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5 g, 21 mmol), distilled water (35 mL), toluene (140 mL), ethyl alcohol (35 mL), 3-thiopheneboronic acid (2.8 g, 22 mmol), sodium carbonate (4.67 g, 44.1 mmol) and tetrakis(triphenylphosphine)palladium (1.22 g, 1.05 mmol) were stirred. This black suspension was heated at 75° C. for 20 h. After cooling to room temperature, the mixture was diluted with distilled water (200 mL) and extracted with ethyl acetate (2×200 mL, then 100 mL). The combined organic phases were dried with MgSO4, filtered and concentrated by rotary evaporation, producing 17 g of a purple oil. Purification by column chromatography on silica gel, using cyclohexane:ethyl acetate (95:5) as eluent, afforded 2.9 g (58%) of white crystals, mp 58° C.