Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16].C(N(CC)CC)C.N1C=CC=CC=1.[S:44](Cl)([CH3:47])(=[O:46])=[O:45]>C(Cl)(Cl)Cl>[S:44]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH3:30])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:16])([CH3:47])(=[O:46])=[O:45]
Reactant: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCOS(C)(=O)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.26 g of N-(12-hydroxydodecyl)-6-(4-ethyl-1-piperazinyl)pyridine-3-carboxamide in 20 ml of chloroform were added 4.2 ml of triethylamine, 5 ml of pyridine and 1.0 ml of mesyl chloride and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed successively with water, 3N-hydrochloric acid and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was chromatographed over a silica gel column to afford 1.11 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](C)(C)[O:18][SiH2]C(C)(C)C)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27]2[S:40][C:39]([CH2:41][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:38][C:28]=2[N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][OH:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:27]2[S:40][C:39]([CH2:41][N:42]3[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]3)=[CH:38][C:28]=2[N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(C)(C)O[SiH2]C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2sc(CN3CCCCC3)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(CO)ccc3n2C(=O)OC(C)(C)C)c2sc(CN3CCCCC3)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To 2-(1-tert-butoxycarbonyl-5-piperidin-1-ylmethyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester [530 mg, 0.78 mmol, Intermediate (83)] in tetrahydrofuran (10 mL) at 0° C. was added a 1M solution of TBAF in tetrahydrofuran (0.86, 0.86 mmol). The mixture was stirred at 0° C. for 2 hours. It was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (n-heptane/ethyl acetate, 80/20 as eluant) to afford 2-(1-tert-butoxycarbonyl-5-piperidin-1-ylmethyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester [305 mg, 70%, Intermediate (84)] as a white foam. LC/MS: 567.3 (M+H), RT=2.89 minutes.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:17][CH:18]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(Cl)cn1
Yield: 99 %

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and commercially available 2,5-dichloropyridine were processed as described in Example 2A to provide the title compound (99% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][CH:14]([OH:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[N:7]3[CH2:15][C:14](=[O:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CC(O)CC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1CCc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of 3-bromo-8-hydroxy-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (1 g, 3.4 mmol, 1 equiv) in THF (30 mL) and DCM (20 mL) at 0° C. was added Dess-Martin reagent (2.9 g, 6.8 mmol, 2 equiv). The resulting mixture was stirred at rt for 3 h. After that, 60 mL of aq. Na2S2O3 was added. The mixture was extracted with ethyl acetate (3×100 mL), dried over Na2SO4. After filtration and concentration, 700 mg of the desired product was obtained, which was directly used for the next step without further purification. MS (ESI): 293, 295 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=O)[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[CH:17][N:18](C)C)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.[NH2:30]N>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[C:16]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[Cl:27])=[CH:17][NH:18][N:30]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN(C)C=C(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: NN
Solvent: CO
Product: Clc1ccccc1-c1c[nH]nc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reaction time: 2 h

Procedure:
Crude 1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)-3-(dimethylamino)prop-2-en-1-one was suspended in methanol (5 mL) and treated with hydrazine (ca. 1 mL). After 2 h, the mixture was concentrated and the residue purified by flash column chromatography to give 276 as colorless solid (527 mg). MS (ESI): 459.0
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:10]=[C:11](/[CH:13]=[C:14](\C)/[C:15]([O:17][CH3:18])=[O:16])[N:12]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH2:41]Br)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=2[CH2:41][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH:10]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[N:12]=3)=[CH:4][CH:3]=2)=[CH:31][CH:32]=1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Reactant: COC(=O)/C(C)=C/c1cn(C2CCCCC2)c(-c2ccc(O)cc2)n1
Product: COC(=O)/C=C/c1cn(C2CCCCC2)c(-c2ccc(OCc3cc(OC)ccc3-c3ccc(Cl)cc3)cc2)n1
Yield: 73.2 %

Procedure:
According to the procedure for preparation of 4.4, phenol 12.9 (60 mg, 0.184 mmol) was alkylated with (4′-chloro-4-methoxy-1,1′-biphenyl-2-yl)methyl bromide (63 mg, 0.202 mmol), to yield 75 mg (73%) of 12.10. MS (ESI) 557.4 (MH+).
Reaction SMILES: [F:1][C:2]1([F:13])[C:11](=[O:12])[N:5]2C(C)(C)[O:7][CH2:8][C@H:4]2[CH2:3]1>O.O1CCOCC1>[F:1][C:2]1([F:13])[CH2:3][C@H:4]([CH2:8][OH:7])[NH:5][C:11]1=[O:12]
Reactant: CC1(C)OC[C@H]2CC(F)(F)C(=O)N21
Solvent: C1COCCO1
Solvent: O
Product: O=C1N[C@@H](CO)CC1(F)F
Temperature: 115 °C
Yield: 89 %

Procedure:
To a solution consisting of (R)-6,6-difluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate 6, 12.5 g, 65.4 mmol) in water-1,4-dioxane (300 mL, 1:1 v/v) was added Amberlite IR-120H* (6.23 g). The reaction mixture was heated to 115° C. for 6 hours and was subsequently filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, using toluene and ethanol additives to help drive off water, to provide a residue. The residue was washed with diethyl ether to afford the title compound as a tan solid (8.8 g; 89%), which was carried on without further purification; TLC Rf 0.25 (solvent system: 70:30 v/v ethyl acetate:hexanes). *Amberlite IR-120H ion-exchange resin, strongly acid gel-type resin with sulfonic acid functionality, CAS: 39389-20-3.75 g of Amberlite was washed and decanted three times with deionized water. The fourth wash was filtered using suction filtration and the semi-dry resin was quickly washed with 2-propanol then diethyl ether. The resin was dried to give 54 g of free flowing dark brown bead resin.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[C:20]([CH:22]=[CH2:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]>CCO.C1COCC1.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([CH2:22][CH3:23])[CH:21]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=Cc1cc(OC)cc(C(Nc2ccc(C#N)cc2)C(=O)OCC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(OC)c1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Pd-C (10%, 236 mg, 0.22 mmol) was added a solution of the ethyl (RS)-(4-cyano-phenylamino)-(3-methoxy-5-vinyl-phenyl)-acetate (1.495 g, 4.44 mmol) obtained in Example 198.3 in EtOH (40 ml) and THF (4 ml) and the mixture was hydrogenated for 1 h. at room temperature. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by filtration over SiO2 (eluent: AcOEt/hexane 1:1). There were obtained 1.5 g (99%) of ethyl (RS)-(4-cyano-phenylamino)-(3-ethyl-5-methoxy-phenyl)-acetate as a beige solid; MS: 338 ([M]+).
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([OH:30])=O)[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:47][O:48][C:49](=[O:57])[C@H:50]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[NH2:51].C(N(CC)CC)C>CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[S:24][CH:25]=[C:26]([C:28]([NH:51][C@H:50]([C:49]([O:48][CH3:47])=[O:57])[CH2:52][C:53]([O:55][CH3:56])=[O:54])=[O:30])[N:27]=4)[CH:21]=3)[C:5]3[CH:33]=[CH:34][C:2]([CH3:1])=[CH:3][C:4]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)cs2)c(=O)[nH]c1=S
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H](NC(=O)c1csc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=S)[nH]c2=O)n1)C(=O)OC
Reaction time: 8 h

Procedure:
The product from example 8(0.4 g) was dissolved in dry dimethylformamide (15 ml) and treated with N,N-carbonyldiimidazole (0.16 g). After 30 minutes L-aspartic acid dimethyl ester (0.32 g) was added followed by triethylamine (0.5 ml). The mixture was stirred overnight and partitioned between ethyl acetate and 2M HCl. The organic phase was washed with brine, dried (MgSO4), evaporated and purified by chromatography eluting with 50% ethyl acetate in dichloromethane. Used directly in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])=[CH:7][C:6]=1[Br:31].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[Br:31][C:6]1[CH:7]=[C:8]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])[CH:9]=[C:10]([O:11][CH2:12][CH3:13])[C:5]=1[O:4][CH2:3][CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCN)c(OCC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCNS(C)(=O)=O)c(OCC)c1
Reaction time: 17 h

Procedure:
A mixture of the product of step c (130.7 mg), triethylamine (93 μl) and methanesulfonyl chloride 21 μl in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 57.1 mg. MS-ESI: [M+H]+=566.0/568.0; HPLC: Rt=12.49 min. (method 1). Diast. ratio: 4:1
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]2[N:8]3[CH:26]=[CH:25][CH:24]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=1)(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[C:1]([C:4]1[CH:28]=[CH:27][C:7]2[N:8]3[CH:26]=[CH:25][CH:24]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(N)=O)ccc1-n1cccc12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C#N)ccc1-n1cccc12
Yield: 42.4 %

Procedure:
A solution of tert-butyl 7′-carbamoylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (2.7 g, 7.1 mmol) and cyanuric chloride (1.3 g, 7.1 mmol) in DMF (10 mL) was stirred at room temperature for 1 hour. The reaction was poured into water and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude mixture that was purified by silica gel chromatography eluting with 0-100% EtOAc in Hexanes. Pure fractions were combined and concentrated to yield tert-butyl 7-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (1.1 g, 44%). ESI-MS m/z calc. 365.4, found 366.3 (M+1)+. Retention time: 2.00 minutes (3 min run).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH2:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH2:22][CH3:23])[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: CCOc1ccccc1N1CCNCC1
Product: CCOc1ccccc1N1CCN(C(=O)Nc2cc(CC)c(C)nc2OC)CC1
Yield: 78 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-ethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH:1][P:2]([CH2:20][CH:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:50](O)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>O1CCCC1>[C:6]1([CH2:5][CH:4]([P:2]([CH2:20][CH:21]([CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:22]([NH:24][C@H:25]([C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:23])([O:1][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:3])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)P(=O)(CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Phenylmethyl N-[2-[[hydroxy[2-phenyl-1-[[(tert-butoxy)carbonyl]amino]ethyl]phosphinyl]methyl]-1-oxo-3-phenylpropyl]-L-phenylalaninate is treated with benzyl alcohol (1.1 eq.) in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine in tetrahydrofuran. After stirring overnight at room temperature, the mixture is filtered and then evaporated to dryness. The residue is taken up in ethyl acetate. This solution is washed 3 times with water, dried over sodium sulphate and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 1/9 dichloromethane/methanol mixture. The product is recovered in a yield of 60%.
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: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c3c1O[C@@H]1C[C@H](O)C=C[C@]31CCN(C)C2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2 mmole (1N 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 pure (+)-galanthamine.
Reaction SMILES: C(OC1C=CC(C=C)=CC=1)(=O)C.C(OC(C)(C)C)(=O)C=C.C([O:27][C:28]12C[CH:32]3[CH2:33][CH:34]([CH2:36][C:30](O)([CH2:31]3)[CH2:29]1)C2)(=O)C(C)=C.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1>[OH:27][CH:28]=[CH:29][C:30]1[CH:36]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Agent: C=CC(=O)OC(C)(C)C
Agent: C=Cc1ccc(OC(C)=O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: OC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask equipped with condenser, thermometer, an argon (Ar) inlet, and a magnetic stirrer bar, the following were added: 4-acetoxystyrene monomer (2.43 grams (g), 0.015 mole), t-butyl acrylate monomer (1.6 g, 0.0125 mole), 3-hydroxy-1-adamantyl methacrylate monomer (5.319 g, 0.0225 mole), 2,2′-azobis(2-methylpropionitrile) (AIBN)(0.328 g, 4% of total moles of monomers), and approximately 40 g of tetrahydrofuran (THF). The reaction mixture was stirred at room temperature and bubbled with Ar flow for 45 minutes before it was heated. The reaction was carried out overnight at 72° C. under an inert Ar atmosphere. The rest of the synthetic procedures are the same as Example 1, except approximately 5 g of concentrated NH4OH was used in deprotecting the acetoxy groups from acetoxystyrene repeat units to form hydroxyl styrene repeat units of the terpolymer.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=C.[Mg].Br[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>O1CCCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:11][CH:12]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C=CCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A suspension of 6-bromo-1-hexene (10 g), magnesium (1 .5g), and lodoethane (1 drop) in anhydrous tetrahydrofuran was heated at reflux until all of the magnesium dissolved. The resulting Grignard reagent was cooled to about 0° C. and was treated with a 1M solution of ZnCl2 in ether (67 ml), and the mixture was allowed to warm to room temperature over 30 minutes. Tetraids(triphenylphosphine)palladium (0) (3.5 g) and 4-bromofluorobenzene (6.73 ml) were added to the reaction and the mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature, concentrated in vacuo, diluted with hexane, filtered and concentrated once more in vacuo. Chromatography on a silica gel column eluting with ether-hexane (0-5%) afforded 5 g of a colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:17])=[CH:12][C:11]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=2)[C:6]([C:4]([OH:5])=[O:3])=[C:14]3[CH2:15][N:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:17])=[CH:29][CH:28]=1)([CH3:32])([CH3:33])[CH3:31]
Reactant: CCOC(=O)CN(C)Cc1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)CN(C)Cc1c(C(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(-c3ccc(C(C)(C)C)cc3)cc12
Temperature: 120 °C

Procedure:
A mixture of 5-(4-tert-butylphenyl)-3-[(ethoxycarbonylmethylmethylamino)methyl]-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (198 mg, 0.36 mmol, see step (d)), NaOH (aq, 1 M, 2 mL) and dioxane (3 mL) was heated at 120° C. for 30 min, cooled, acidified with HCl (aq, 1 M) to pH 5 and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to afford the sub-title compound. Yield 184 mg (98%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.C[O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:4]([C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([OH:30])=[O:21])=[CH:11][CH:12]=1)([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: COC(=O)c1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2C(=O)O)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-hydroxy-benzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C19H20O7 [M+Na]+: 383.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)[CH:8]=[CH:7]2
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Br)c2c(ccn2Cc2ccc(C(F)(F)F)cc2)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
7-bromo-5-fluoro-1H-indole (900 mg, 4.20 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.6 g, 6.7 mmol) were dissolved in DMF (20 ml). The mixture was cooled to −10° C. and NaH (185 mg, 4.6 mmol) was added portion wise over 5 min. The mixture was stirred for 1 hour at this temperature. Quenched with NH4Cl (½ sat.) and 1N HCl. The mixture was diluted with water and the aqueous phase was extracted 3× with ether. The combined organic layers were washed with 3× water, 1× brine and dried over MgSO4. The product was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 7.70 (m, 3H), 7.45 (dd, 1H), 7.25 (dd, 1H), 7.10 (d, 2H), 6.65 (d, 1H), 5.90 (s, 2H).