Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC.[BH4-].[Na+].[Li+].[Cl-].C([O:13][C:14](=O)[CH2:15][C:16]([C:31]#[N:32])([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)C>O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)([CH2:15][CH2:14][OH:13])[C:31]#[N:32])=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(C#N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: N#CC(CCO)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
Ethylene glycol dimethyl ether (10 ml) was treated with sodium borohydride (142 mg) and LiCl (228 mg) and the mixture stirred for 30 min. 3-Cyano-3,3-bis-(4-fluoro-phenyl)-propionic acid ethyl ester (847 mg) was added and the mixture stirred for 6 hrs, before more sodium borohydride (36 mg) and LiCl (57 mg) were added and stirring continued overnight. The mixture was poured into water and extracted (3×) with ethyl ether. The combined organic extracts were dried over Na2SO4. Filtration, concentration and flash chromatography of the residue afforded the title compound (41%; Isolated as an oil).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:15][C:10]1[CH:11]=[N:12][N:13]([CH3:14])[C:9]=1[N:7]1[CH2:8][C:2]([F:26])([F:1])[CH2:3][CH:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:5][CH2:6]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1ncc(N)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (2.5 g, 6.67 mmol) in ethanol (100 mL) and water (10 mL) was added ammonium chloride (3.5 g, 65.0 mmol) and iron powder (3.0 g, 53.7 mmol). The reaction mixture was heated at 100° C. for 2.5 hr, before being cooled down at room temperature, filtered through Celite®, washed with MeOH and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (200 mL), quenched with a saturated solution of sodium hydrogencarbonate (300 mL) and a 10% solution of sodium sulfite (100 mL) and the mixture stirred for 30 min. The layers were separated and the aqueous layer extracted with DCM (100 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as an orange foam (2.12 g). A solution of PyBOP (1.92 g, 3.70 mmol) and 2-bromo-5-(tert-butoxycarbonyl-amino)thiazole-4-carboxylic acid (795 mg, 2.46 mmol) in DCM (50 mL) was stirred at room temperature for 15 min. tert-Butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate (850 mg, 2.46 mmol) and DIPEA (2.0 mL, 11.4 mmol) were added and the mixture stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL) and washed with a saturated solution of sodium hydrogencarbonate (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(4-(5-(tert-butoxycabonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate as a pale yellow foam (1.35 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.37 (s, 1H), 7.65 (s, 1H), 4.88 (s, 1H), 4.04 (s, 1H), 3.77 (s, 3H), 3.63-3.43 (m, 2H), 3.38-3.24 (m, 2H), 2.52-2.40 (m, 2H), 2.13-2.05 (m, 1H), 1.99 (s, 1H), 1.53 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:57][CH2:58][CH2:59][CH2:60]O>C(Cl)Cl>[Br:57][CH2:58][CH2:59][CH2:60][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[C:14]([F:13])=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:37])=[CH:16]4)=[N:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Diethyl azodicarboxylate (557 μl, 3.53 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (1 g, 2.95 mmol), triphenylphosphine (1.15 g, 4.42 mmol) and 3-bromo-1-propanol (293 ul, 3.24 mmol) in methylene chloride (25 ml). The mixture was stirred at ambient temperature for 1 hour and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the solid was filtered, washed with diethyl ether and evaporated to give 7-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (1.35 g, 100%).
Reaction SMILES: [C:1]([NH:6][C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:5])[CH2:2][CH2:3][CH3:4]>CO.[C].[Pd]>[NH2:17][C:16]1[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)Nc1c(N)cccc1C(=O)OC
Yield: 99.7 %

Procedure:
[step 1] To methyl 2-aminobenzoate (1.5 g, 9.92 mmol) was added butyric anhydride (4.9 mL, 29.76 mmol), and the mixture was stirred at room temperature for 2 hr. Under ice-cooling, fuming nitric acid (1.6 mL) was added dropwise to the mixture, and the mixture was stirred at 0° C. for 20 min. The mixture was adjusted to pH 7 with water and 4 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate (150 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 60/40) to give methyl 2-butyramido-3-nitrobenzoate (1.26 g, 48%). [step 2] Methyl 2-butyramido-3-nitrobenzoate (1.65 g, 6.2 mmol) obtained in step 1 was dissolved in methanol (34 mL), and the mixture was stirred in the presence of 10% palladium carbon (413 mg) under a hydrogen atmosphere at room temperature for 6 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give methyl 3-amino-2-butyramidobenzoate (1.46 g, 100%). [step 3] To methyl 3-amino-2-butyramidobenzoate (1.46 g, 6.2 mmol) obtained in step 2 was added acetic acid (9.0 mL), and the mixture was stirred at 80° C. for 1.5 hr. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (300 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 50/50) to give the title compound (1.18 g, 87%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22](OC)=[O:23])[CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCOCC.O>[CH2:7]([O:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH2:22][OH:23])[CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC/C=C\CCCOc1cccc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCCCCC/C=C\CCCOc1cccc(CO)c1
Yield: 99.9 %

Procedure:
35 mg of lithium aluminum hydride (922 μmol) are added, at 0° C., to 140 mg of 15 (460 μmol) in ether (3 mL). After reaction for 1 hour 30 minutes, the reaction medium is diluted with ether and hydrolyzed with two drops of water. After filtering through Celite, drying over Na2SO4 and concentrating, 127 mg of a colorless oil are isolated, i.e. a yield of 99%.
Reaction SMILES: O.O.C1(S([O-])=O)C=CC=CC=1.[Na+].Cl.C1(C)C=CC=CC=1.C(O)C.[CH:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH:38]=[CH:39][C@H:40]3[CH2:45][CH2:44][C@H:43]([CH2:46][CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH2:42][CH2:41]3)[CH2:34][CH2:33]2)[CH2:28][CH2:27]1)=[CH2:25]>O>[CH:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C@H:32]2[CH2:33][CH2:34][C@H:35](/[CH:38]=[CH:39]/[C@H:40]3[CH2:45][CH2:44][C@H:43]([CH2:46][CH2:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH2:42][CH2:41]3)[CH2:36][CH2:37]2)[CH2:28][CH2:27]1)=[CH2:25]
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](C=C[C@H]3CC[C@H](CCCc4ccccc4)CC3)CC2)CC1
Agent: Cl
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/[C@H]3CC[C@H](CCCc4ccccc4)CC3)CC2)CC1

Procedure:
A mixture prepared by adding 5.9 g (29.5 mmol) of sodium benzenesulfinate dihydrate, 5 ml of 6N hydrochloric acid, and 40 ml of mixed solvent of toluene/ethanol (1/1) to 6.1 g (14.5 mmol) of the crude 4-(trans-4-(2-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)vinyl)cyclohexyl)propylbenzene was refluxed for 40 hours. Water in an amount of 30 ml was added to the reaction mixture, extracted with 150 ml of toluene, washed with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: heptane/toluene=95/5) to obtain 3.8 g of a crude (E)-4-(trans-4-(2-(trans-4-(trans-4-vinylcyclohexyl)cyclohexyl)-vinyl)cyclohexyl)propylbenzene. This product was recrystallized from a mixed solvent of ethanol/ethyl acetate to obtain 1.1 g of the subjective compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32]([C@H:34]1[NH:46][CH2:45][C:37]2[NH:38][C:39]3[C:44]([C:36]=2[CH2:35]1)=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32]([C@H:34]1[NH:46][CH2:45][C:37]2[NH:38][C:39]3[C:44]([C:36]=2[CH2:35]1)=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C([C@@H]1Cc2c([nH]c3ccccc23)CN1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
197 mg (0.3 15 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((3S)-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3-yl)carbonyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers are reacted with 48 mg (1.26 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR47## is obtained as mixture of diastereomers in the form of white foam. TLC: methylene chloride/methanol/conc. ammonia (350:50:1) Rf =0.50, FD-MS: M+ =529.
Reaction SMILES: Br[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=2[CH:3]=1.[F:18][C:19]([F:24])([F:23])C([O-])=O.[K+]>CN(C)C=O.C1(C)C=CC=CC=1.[Cu]I>[F:18][C:19]([F:24])([F:23])[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=2[CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CCOC(=O)c1csc2cc(OC)c(Br)cc12
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc2cc(OC)c(C(F)(F)F)cc12
Yield: 54.8 %

Procedure:
Ethyl-5-bromo-6-methoxybenzo[b]thiophene-3-carboxylate (D4) (0.81 g, 3 mmoles) in dry dimethylformamide (20 ml) and toluene (10 ml) was treated with potassium trifluoroacetate (0.78 g, 6 mmoles) and copper (I) iodide (0.98 g, 6 mmoles). The mixture was heated under reflux for 1 hr using a Dean-Stark trap to collect the toluene. The mixture was cooled and poured into water (150 ml) and extracted with diethyl ether. The resulting emulsion was filtered through kieselguhr. The combined organic extracts were washed several times with water then dried (Na2SO4). Flash chromatography on TLC silica gel eluting with dichloromethane/60-80 petrol ether 1:1 gave the title compound (D6) (0.5 g, 64%)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH3:19][NH:20][CH2:21][C:22]#[CH:23]>>[CH3:19][N:20]([CH2:21][C:22]#[CH:23])[C:13]([C:11]1[S:12][C:8]([C:5]2[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:9][CH:10]=1)=[O:15]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C#CCNC
Product: C#CCN(C)C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and N-methyl propargylamine by the method described in Example 2 method B. Colorless solid (128 mg, 98%). 1H NMR (CDCl3) 2.37 (d, J=1.8, 3H), 3.28 (br s, 3H), 4.34 (br s, 2H), 7.48 (d, J=3.5, 1H), 7.51 (br d, 1H). 19F NMR −63.13. LC/MS 6.36 min, [M+1]+ 329.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29](I)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=[CH:12]3)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(I)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)C1

Procedure:
This compound was prepared from 1-benzenesulfonyl-5-iodo-1H-indole and 3-iodoazetidin-1-carboxylic acid tert-butyl ester by the method outlined under 1.b). ESI-MS [m/z]: 357.05 [M-(C4H9)+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14][NH:15][C:16]([O:18]C(C)(C)C)=O)[CH3:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[C:16]([NH:15][NH:14][C@@H:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=1)[CH3:13])(=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccc(C(C)NNC(=O)OC(C)(C)C)cc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc([C@@H](C)NNC(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Thus the slow moving enantiomer tert-butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate (0.74 g, 2.42 mmol) from a chiral separation as described above was treated with TFA/CH2Cl2 (1:1, 10 mL) for 1 h at r.t. The reaction was concentrated on a rotovap and the residual TFA was removed by co-evaporation from toluene. The resulting ethyl 4-(1-hydrazinoethyl)benzoate was then dissolved in CH2Cl2 (15 mL) and cooled to −78° C. A solution of benzoyl chloride (365 μL, 3.15 mmol) and 2,6-di-tert-butyl-4-methylpyridine (745 mg, 3.63 mmol) in CH2Cl2 (5 mL) was added slowly at −78° C. After 3 h at −78° C., the reaction mixture was loaded quickly on a SiO2 column and eluted with 30% EtOAc/hexane. Fractions containing product were concentrated and purified further on HPLC using Kromasil C8 column (10% to 70% CH3CN/H2O/0.1% TFA, 12 min), and again on silica gel column (30% EtOAc/Hexane) to give (R)-(+)-ethyl 4-[1-(2-benzoylhydrazino)ethyl]benzoate. HPLC/MS: m/z=313.3 (M+1)+, Rt=3.08 min. Daicel column Chiralcel OJ, 40° C., 0.5 mL/min, 10% isopropanol/90% n-heptane: t 35.79 min; [α]D20=+192.4° (cl, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.03 (2H, d, J=8.0 Hz), 7.94 (1H, br s), 7.66 (2H, d, J=7.5 Hz), 7.51 (1H, t, J=7.5 Hz), 7.54 (2H, d, J=8.0 Hz), 7.40 (2H, t, J=8.0 Hz), 4.39 (2H, q, J=7.0 Hz), 4.36 (1H, q, J=7.0 Hz), 1.46 (3H, d, J=6.0 Hz), 1.41 (3H, t, J=7.0 Hz); 13C NMR (500 MHz, CDCl3): δ 167.76, 166.69, 148.16, 132.70, 132.27, 130.21, 130.18, 128.94, 127.47, 127.15, 61.22, 60.21, 21.21, 14.58. (S)-(−)-ethyl 4-[1-(2-benzoylhydrazino)ethyl]-benzoate was similarly prepared from the faster moving isomer of tert-butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate. HPLC/MS: m/z=313.4 (M+1)+, Rt=3.09 min. Daicel column Chiralcel OJ, 40° C., 0.5 mL/min, 10% isopropanol/90% n-heptane: t 34.99 min; [α]D20=−194.4° (cl, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.02 (2H, d, J=8.0 Hz), 7.73 (1H, br s), 7.65 (2H, d, J=8.0 Hz), 7.49 (1H, t, J=8.0 Hz), 7.48 (2H, d, J=8.0 Hz), 7.39 (2H, t, J=8.0 Hz), 4.38 (2H, q, J=7.0 Hz), 4.34 (1H, q, J=7.0 Hz), 1.44 (3H, d, J=6.5 Hz), 1.41 (3H, t, J=7.0 Hz); 13C NMR (500 MHz, CDCl3): δ 167.81, 166.74, 148.73, 132.92,132.15, 130.13, 130.02, 128.90, 127.43, 127.12, 61.20, 60.09, 21.52, 14.58.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10]2)=[O:4].[OH-].[K+].Cl>O.CN(C=O)C>[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10]2)([OH:4])=[O:2]
Reactant: COC(=O)COc1ccc2cc(C(=O)OC)ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2cc(OCC(=O)O)ccc2c1
Yield: 77.9 %

Procedure:
2.3 g of methyl 6-methoxycarbonylmethoxy-2-naphthoate and 2.3 g of KOH are heated under reflux for 3 h in 100 ml of water and 10 ml of DMF. The mixture is then acidified to pH 0.3 using hydrochloric acid, and the precipitate which is deposited is filtered off with suction at RT. 1.7 g of methyl 6-carboxymethoxy-2-naphthoate are obtained;
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19](O)=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(COC)OC.O>[CH2:12]([O:11][CH2:10][C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:19][OH:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](CO)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
N-BOC-O-benzylserine (5.0 g, 16.9 mmol) in 30 mL dimethoxyethane was treated with 4-methylmorpholine (2.0 mL, 18.6 mmol) and cooled to 0° C. The solution was treated with isobutylchloroformate (2.3 mL, 17.8 mmol) and the resulting suspension stirred for 15 minutes, then filtered. The solids collected were washed with 2 portions of dimethoxyethane and the washings combined with the original filtrate. This material was cooled in an ice bath and treated with a cold solution of sodium borohydride (1.93 g, 50.8 mmol) in 40 mL 1/2 saturated sodium bicarbonate and the reaction stirred for 2 hours. The mixture was diluted with water and extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate, water and brine, dried, filtered and concentrated to provide the title compound. MS (DCI, NH3): 282 (MH+); 299 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:12][C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)(C(OC)=O)[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH3:1][O:2][CH:3]([CH2:12][C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(OC)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OC
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of dimethyl 2-methoxy-2-((1-trityl-1H-imidazol-4-yl)methyl)malonate (0.1520 g, 0.31 mmol) and sodium chloride (0.0398 g, 0.68 mmol) in NMP (2 mL) and water (0.3 mL) was heated to 201° C. for 1 hr. After cooling to room temperature, ethyl acetate (15 mL) was added and the organic layer was washed with water (2×10 mL), saturated sodium chloride (1×10 mL) and then dried over NaSO4. Solvent removal yielded 0.1030 g of crude product. This was purified by chromatography on a silica gel 60 (11 g, 0.040 to 0.063 mm particle size) column (2.5×10 cm) using CHCl3/MeOH (98:2) as the eluent and collecting 12 mL fractions. Fractions 2 to 10 were pooled and dried, and the residue was re-purified as above, except that 5 g of silica gel was used and the eluent was CHCl3/MeOH (99:1). Fractions 10 to 16 were pooled and afforded, after drying, 0.0592 g (45%) of 94.5% pure methyl 2-methoxy-3-(1-trityl-1H-imidazol-4-yl)propanoate; retention time, 7.29 min.; column: YMC ODS-A (3 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. LC/MS: ESI (M+H)+=427.1.
Reaction SMILES: [ClH:1].[C:2]([C@H:6]1[C@@H:12]([O:13]CC2C=CC=CC=2)[CH2:11][C@H:10]2[N:21]([CH3:22])[C@@H:7]1[CH2:8][CH2:9]2)([O:4]C)=[O:3]>Cl>[OH:13][C@H:12]1[CH2:11][C@H:10]2[N:21]([CH3:22])[C@H:7]([CH2:8][CH2:9]2)[C@H:6]1[C:2]([O-:4])=[O:3].[ClH:1]
Reactant: COC(=O)[C@H]1[C@@H](OCc2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)[O-])[C@@H](O)C2

Procedure:
(1R,2R,3S)-2-Carbomethoxy-3-benzoxytropane, hydrochloride (100 g, 0.29 mol) was refluxed in 1000 ml 1M hydrochloric acid for 18 hours and the solution was ice cooled. Benzoic acid was collected by filtration and the filtrate was concentrated in vacuo. Trituration of the remanescens with ethanol and filtration yields (1R,2R,3S)-3-hydroxy-tropane 2 carboxylate, hydrochloride as a white crystalline compound which without further purification was dried and refluxed in phosphorous oxychloride (50 ml) for two hours. The solution was concentrated in vacuo and absolute methanol (150 ml) was slowly added under ice cooling. The solution was stirred at ambient temperature for 16 hours and was concentrated in vacuo. The remanescens was ice cooled and made basic by addition of a sodium hydroxide solution (10M, approximately 100 ml) and was extracted 5 times with diethyl ether. The combined organic phase was dried and concentrated in vacuo yielding an oil, which was distilled in vacuo (70°-74° C., 1 mBar) yielding the title compound as a clear oil.