Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:11]2[C:6]([C:7]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)=[CH:5][CH:4]=1.[C:23]([S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:26])([CH3:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[C:23]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([N:18]2[CH2:17][CH2:16][C:7]3([C:6]4=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[N:11]4[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[O:8]3)[CH2:20][CH2:19]2)=[O:35])=[CH:37][CH:38]=1)(=[O:29])=[O:28])([CH3:26])([CH3:25])[CH3:24]
Reactant: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Reactant: CC(C)(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.5 %

Procedure:
1′-(Trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (172 mg, 0.559 mmol), 4-tert-butylsulfonylbenzoic acid (176 mg, 0.727 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (150 mg, 0.783 mmol), and triethylamine (312 μL, 2.24 mmol) were combined in dichloromethane (3.4 mL). The reaction mixture was allowed to stir for 72 hours at room temperature. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water to yield (4-tert-butylsulfonylphenyl)-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (49 mg, 16%) as a white solid. ESI-MS m/z calc. 532.2. found 533.5 (M+1)+. Retention time: 2.10 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.89 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.35-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.03 (d, J=3.9 Hz, 1H), 6.40 (d, J=3.9 Hz, 1H), 4.53-4.37 (m, 1H), 3.57-3.14 (m, 3H), 2.17-1.78 (m, 4H), 1.26 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([O:31][C@@H:32]([CH3:37])[C:33]([F:36])([F:35])[F:34])=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([O:16]C(C)(C)C)=[O:15]>ClCCl>[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([O:31][C@@H:32]([CH3:37])[C:33]([F:35])([F:36])[F:34])=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)cc1Cl)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
Trifluoroacetic acid (4.4 mL, 58.7 mmol) was added to a solution of (S)-tert-butyl 5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)oxy)-2-fluorobenzoate (Preparation 298, 9.2 g, 19.6 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 20 hours then concentrated in vacuo. The crude was purified by silica gel chromatography, eluting with heptane:ethyl acetate (from 95:5 to 40:60), to provide the title compound as a white solid (6.9 g, 85%).
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([C:9]2([OH:19])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:7][N:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:19][C:9]1([C:6]2[S:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][CH:7]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: CC(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Yield: 107.8 %

Procedure:
A solution of 8-(2-isopropyl-1,3-thiazol-5-yl)-1,4-dioxaspiro[4.5]decan-8-ol (0.714 g, 2.52 mmol) in 15 mL of THF/1N HCl (1:1) was stirred overnight at room temperature. The mixture was treated with Na2CO3 to PH 8 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.65 g of 4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexanone in 98% yield. MS (EI) calcd: (M+H)+=240.1; found: 240.0.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[I:8][C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH2:18])=[CH:11][CH:10]=1.O>C(O)(=O)C>[I:8][C:9]1[C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]([NH:18][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)c2c1OCO2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(I)c2c1OCO2
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Acetic anhydride (14.25 ml) was added dropwise to a mixture of intermediate 18 (36.6 g) in acetic acid (500 ml), stirred at room temperature. The reaction mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured out into water (500 ml). The precipitate was filtered, washed with water, then dried, yielding 39.29 g (92.6%) of N-(7-iodo-1,3-benzodioxol-4-yl)acetamide (intermediate 19).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[N:17][C:18]5[C:23]([CH:24]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:13][C:14]=3[C:5]=2[N:4]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40]C(C)(C)C)=O)[CH2:34][CH2:33]3)=[C:28]([C:45]([F:48])([F:47])[F:46])[CH:27]=2)[C:3]1=[O:49].Cl.CN(C(ON1N=N[C:61]2C=CC=N[C:60]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(=O)CC.CCN(C(C)C)C(C)C>CCO.O1CCOCC1.CN(C=O)C>[CH3:1][N:2]1[CH2:25][C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[N:17][C:18]5[C:23]([CH:24]=4)=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:13][C:14]=3[C:5]=2[N:4]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH2:60][CH3:61])[CH2:34][CH2:33]3)=[C:28]([C:45]([F:46])([F:47])[F:48])[CH:27]=2)[C:3]1=[O:49]
Reactant: CN1Cc2cnc3ccc(-c4cnc5ccccc5c4)cc3c2N(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCC(=O)O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCN(c2ccc(N3C(=O)N(C)Cc4cnc5ccc(-c6cnc7ccccc7c6)cc5c43)cc2C(F)(F)F)CC1
Reaction time: 4 h
Yield: 17 %

Procedure:
To a solution of tert-butyl 4-(4-(3-methyl-2-oxo-9-(quinolin-3-yl)-3,4-dihydropyrimido[5,4-c]quinolin-1(2H)-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (32 mg, 0.047 mmol) in EtOH (1 mL) at room temperature was added a solution of hydrochloric acid in dioxane (4M, 2 mL). The resulting solution was allowed to stir for 4 h. After removal of solvents in vacuo, the residue was redissolved in DMF (2 mL), to which HATU (53 mg, 0.14 mmol), propionic acid (8 μL, 0.094 mmol), and DIEA (24 μL, 0.14 mmol) were added. The resultant solution was stirred for 4 h before filtration. The crude product was subjected to LC-MS-HPLC purification to afford 5 mg of product. LC-MS: (M+H)=9025.22.
Reaction SMILES: [C:1](=[N:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([CH2:13][CH3:14])=[C:7]([N:15]=[C:16]([CH3:18])[CH3:17])[C:6]=1[CH3:19])([CH3:3])[CH3:2].C(O)C>[Pt].C(OCC)(=O)C>[CH:16]([NH:15][C:7]1[C:8]([CH2:13][CH3:14])=[CH:9][C:10]([CH2:11][CH3:12])=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[C:6]=1[CH3:19])([CH3:17])[CH3:18]
Reactant: CCc1cc(CC)c(N=C(C)C)c(C)c1N=C(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(CC)c(NC(C)C)c(C)c1NC(C)C
Reaction time: 1.2 h
Yield: 94 %

Procedure:
N,N′-diisopropylidene-[diethyl(methyl)-1,3-benzenediamine] (3.17 g) and Pt(S)/C (0.3 g) were added to a mixture of ethanol (20 g) and ethyl acetate (20 g) in an autoclave. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The mixture was kept at 22° C. and 0-125 psi (0 to 8.62×105 Pa) of H2 for 1.2 hours, forming the corresponding N,N′-diisopropyl-[diethyl(methyl)-1,3-benzenediamine] in 94% yield. Six percent of the diimine was underhydrogenated; conversion of the diimine was 100%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:30]([OH:42])[C@@:29]2([CH3:43])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([O:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[C:30](=[O:42])[C@@:29]2([CH3:43])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O[Si](C)(C)C)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)-11-(trimethylsilyloxy)spirostan-12-ol was oxidized with chromium trioxide and pyridine in methylene chloride according to the procedure described in Org. Syn., 1976, 55, 84 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(C)c1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccc(C)c1)CCCC3
Yield: 72.5 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.310 g; 0.87 mmol), LHMDS 1N in THF (0.96 mL; 0.96 mmol), 1-iodopropane (0.13 mL; 1.5 mmol) in DMF (3.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.257 g (73%) of the title compound as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:6]1.[N:31]1[CH:36]=CC=C[CH:32]=1.CS(OS(C)(=O)=O)(=O)=O.CNC>C1COCC1>[CH3:32][N:31]([CH3:36])[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=2[C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:6]1
Reactant: c1ccncc1
Reactant: O=C1NC(=O)C(c2cn(CCCO)c3ncccc23)=C1c1cccc2ccccc12
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CN(C)CCCn1cc(C2=C(c3cccc4ccccc34)C(=O)NC2=O)c2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a solution of Compound 3 (25 mg, 0.063 mmol) in THF (5 mL) was added pyridine (24.9 mg, 0.315 mmol). The mixture was stirred at room temperature for 15 min and then methanesulfonic anhydride (43.9 mg, 0.25 mmol) was added and the mixture was heated to 50° C. for 2 h. TLC and mass spectra shown the formation of Compound 4a. To the crude product was added excess 1.0 M solution of dimethylamine in THF (1 mL). The mixture was heated from 50 to 65° C. overnight. The solvent was concentrated in vacuo. The crude product was extracted with ethyl acetate (100 mL). The organic phase was washed with saturated NaHCO3, brine, and evaporated in vacuo to give a crude product (50 mg). The crude product was separated by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, from 98:2:0.2 to 95:5:0.5) to give 6 mg (22%) of Compound 4 as a yellow solid. 1H NMR (CDCl3) δ 8.33 (s, 1H), 8.08 (dd, J=1.5, 4.7 Hz, 1H), 7.94 (m, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.54 (m, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.28 (m, 1H), 6.44 (dd, J=4.7, 8.1 Hz, 1H), 6.26 (dd, J=1.5, 8.0 Hz, 1H), 4.37 (t, J=7.1 Hz, 2H), 2.29 (t, J=7.0 Hz, 2H), 2.25 (s, 6H), 2.07 (m, 2H). ES-MS m/z 425 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[Na+]>C(#N)C.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[C:19]([CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][N:7]([CH3:8])[C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])#[N:20]
Reactant: [C-]#N
Reactant: CN(Cc1cccc(CBr)c1)C(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(Cc1cccc(CC#N)c1)C(=O)OC(C)(C)C

Procedure:
tert-Butyl-N-[3-(bromomethyl)benzyl]-N-methylcarbamate (preparation 13) (3.2 g, 10.18 mmol) was dissolved in acetonitrile (50 ml) and treated with sodium cyanide (1.23 g, 25.10mmol) followed by benzyl triethylammonium bromide (220 mg, 0.8 mmol) and the resultant mixture stirred at room temperature for 4 days. The resultant slurry was diluted with ethyl acetate (200 ml) washed with water, sat aq brine and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a pale yellow solid which was purified by chromatography (SiO2, eluting with 100% CH2Cl2) to give the desired product with a trace of impurity (3.0 g). 1H NMR (CDCl3) δ 1.50 (s, 9H), 2.80 (s, b, 3H), 3.75 (s, 2H), 4.40 (s, 2H), 7.20 (m, 3H), 7.35 (t, 1H). LRMS m/z=278.1 (M+18)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[S:11]([OH:14])(=[O:13])=[O:12].C(Cl)(Cl)Cl.[N+:19]([O-])([OH:21])=[O:20]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][C:4]=1[S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(S(=O)(=O)O)c(OC)c1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
To a solution prepared by adding 90 g of 2,4-dimethoxybenzenesulfonic acid obtained in Step (1) above to 200 ml of chloroform, was added 225 ml of nitric acid (d=1.42) with stirring. The reaction mixture was stirred at 25° to 30° C. for 2 hours and 300 ml of acetonitrile was added thereto. The crystals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:71])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[N:63]=[C:64]([NH:67]C(=O)C)[S:65][CH:66]=2)=[CH:58][CH:57]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl>>[CH3:1][O:2][C:3](=[O:71])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[N:63]=[C:64]([NH2:67])[S:65][CH:66]=2)=[CH:58][CH:57]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(-c2csc(NC(C)=O)n2)cc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(-c2csc(N)n2)cc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-[4-(2-Acetylamino-thiazol-4-yl)-benzenesulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was treated with HCl according to General Procedure N to give (S)-2-({(S)-7-[4-(2-Amino-thiazol-4-yl)-benzenesulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This was hydrolyzed according to General Procedure B to give the title compound (20 mg). LCMS (m/z): 972.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:23])[C:3]([OH:24])=[O:2])=[CH:6][CH:7]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(OCCOc2ccc(C(=O)C(=O)O)cc2)cc1
Yield: 88.2 %

Procedure:
A mixture of 4-[[2-(4-methoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.77 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction with dichloromethane provided material which solidified and was crystallized from diethyl ether-hexane to give 0.65 g of colorless 4-[[2-(4-methoxyphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid, mp 138°-139° C.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][N:16]1[CH2:33][C:31]2=[C:32]3[C:27](=[C:28]([O:34][CH3:35])[CH:29]=[CH:30]2)[O:26][C@@H:25]2[C@:19]3([CH:20]=[CH:21][C:22]([CH2:24]2)=[O:23])[CH2:18][CH2:17]1.CO>C1COCC1.C(Cl)(Cl)Cl>[CH3:15][N:16]1[CH2:33][C:31]2=[C:32]3[C:27](=[C:28]([O:34][CH3:35])[CH:29]=[CH:30]2)[O:26][C@@H:25]2[C@:19]3([CH:20]=[CH:21][C@H:22]([OH:23])[CH2:24]2)[CH2:18][CH2:17]1
Reactant: COc1ccc2c3c1O[C@H]1CC(=O)C=C[C@@]31CCN(C)C2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
2 mmole (1 N in tetrahydrofuran {THF}) of L-Selectride® (lithium tri-sec-butylborohydride, Aldrich)is charged into 8 ml THF and cooled to -78° C. 1 mmole of (-)-narwedine in 50 ml THF is added dropwise over a period of 30 minutes. After addition, the solution is stirred at -78° C. for 2 hours and then warmed to 0° C. 0.4 ml of methanol is added and the solution is warmed to 25° C. and stirred for 15 minutes. Solvent is then evaporated under vacuum to dryness to obtain a syrup. The syrup is dissolved in 0.5 ml CHCl3 and the solution is loaded into a SiO2 200-400 mesh, 6A, column. The column is eluted with a solvent mixture of CH2Cl2 /CH3OH 6:1 to obtain 286 mg of pure (-)-galanthamine (a yield of 99.5%). HPLC of the resultant mixture indicates there is no epigalanthamine or lycoramine present. {m.p. 128°-129° C.; [α]D25 =-93.4}. Natural (-)-galanthamine has a melting point of 126°-127° C. ([α]D25 =-91.0)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.CN(C)[C:16](=[O:18])[CH3:17].[NH4+].[Cl-]>C1CCCCC1.CCOCC>[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:18])[CH3:17]
Reactant: Brc1cccc(Br)n1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(=O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of 3.00 g (12.7 mmol) of 2,6-dibromopyridine in 20 mL anhydrous. Et2O at −78° C. was added dropwise over 30 rnin. 8.0 mL (12.8 mmol) of 1.6 M n-BuLi in cyclohexane. After stirring for 3 h at −78° C., 8.2 mL (88 mmol) of N,N-dimethylacetamide was added dropwise and the solution was stirred at −78° C. for 1 h. On warming to RT, Et2O (100 mL) and saturated aqueous NH4Cl (50 mL) were added and the layers were separated. The organic layer was dried over NaSO4 and the volatiles were removed by rotary evaporation. The resulting yellow solid was recrystallized from hexanes to provide 1.8 g (71 %) of 2-acetyl-6-bromopyridine as colorless crystals. 1H NMR (CDCl3): δ 2.81 (s, 3H); 7.67-7.77 (m, 2 H); 8.22 (dd, J=6.8, 1.6 Hz, 1 H). Mass Spec.: m/e 200.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[C:38]([F:46])=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=3)[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:47]([C:51]1[S:52][CH:53]=[C:54]([C:56](O)=[O:57])[N:55]=1)[CH:48]([CH3:50])[CH3:49].C(N(CC)CC)C>CN(C=O)C>[F:46][C:38]1[C:39]([CH2:43][CH2:44][OH:45])=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:56]([C:54]3[N:55]=[C:51]([CH2:47][CH:48]([CH3:50])[CH3:49])[S:52][CH:53]=3)=[O:57])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: CC(C)Cc1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4F)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.2 g) was added to a solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.13 g), 2-isobutylthiazole-4-carboxylic acid (example 72, step d) (0.08 g) and triethylamine (0.23 mL) in DMF (7 mL) at 0° C. and the resulting yellow solution allowed to warm to RT and was stirred for 2 h. The mixture was partitioned between ethyl acetate and brine (100 mL), the organic phase was washed with brine (2×100 mL), dried over sodium sulphate, filtered and then evaporated. The resulting gum was purified by silica gel chromatography eluting with 47.5:47.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient. The fractions containing product were combined, toluene (200 mL) was added, and the solvent evaporated under reduced pressure to give the subtitled compound as a clear gum. Yield 0.24 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]2[C:12]([CH:13]=1)=[C:11]([N+:14]([O-])=O)[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)=[O:4].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]2[C:12]([CH:13]=1)=[C:11]([NH2:14])[C:10]([O:17][CH3:18])=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c([N+](=O)[O-])c(OC)ccc2n1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc2c(N)c(OC)ccc2n1C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 9 (1.0g, 3.78 mmol) in anhydrous methanol (90 mL) was added 10% Pd/C (150 mg) suspended in anhydrous methanol (15 mL) followed by ammonium formate (1.10 g, 17.4 mmol). The reaction mixture was stirred for 1 h, filtered through celite and the methanol removed. The residue was taken up in CH2Cl2/H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and evaporated to afford 10 (595 mg, 67%) as a brown solid which was used without further purification; 1H NMR (CDCl3): δ 7.21 (1H, s), 7.06 (1H, d), 6.72 (1H, d), 4.01 (3H, s), 3.90 (3H, s), 3.88 (3H, s).