Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:9]([NH:11][C@H:12]([C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C(OCC)(=O)C>[NH2:1][C@@H:2]([C:9]([NH:11][C@H:12]([C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)c1ccccc1
Yield: 100 %

Procedure:
Condensation of BocDPhgOH (5.0 g.) and HPheOMe hydrochloride salt (4.3 g.) by the mixed anhydride method using isobutyl chloroformate gave BocDPhg-PheOMe in 98% yield. De-t-butoxycarbonylation of BocDPhg-PheOMe (4.23 g.) using hydrogen chloride in ethyl acetate gave HDPhg-PheOMe in 100% yield. Condensation of BocProOPFP (3.81 g.) and HDPhg-PheOMe hydrochloride salt (3.5 g.) by the activated ester method gave BocPro-DPhg-PheOMe in 74% yield. Hydrazinolysis of Bocpro-DPhg-PheOMe (3.57 g.) gave BocPro-DPhg-PheNHNH2 in 80% yield.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[CH2:23][N:22]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:21]([C:36]([OH:38])=[O:37])[CH2:20]2.O>CN(C=O)C.[Na+].[I-]>[CH2:1]([O:38][C:36]([C@@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=2)[CH2:23][N:22]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C2
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)CN(C(=O)OC(C)(C)C)[C@H](C(=O)OCc1ccccc1)C2
Temperature: 45 °C
Reaction time: 5 h
Yield: 93.8 %

Procedure:
Benzyl chloride (116.4 g, 0.92 mol), powdered K2CO3 solids (87 g, 0.63 mol), NaI (6.0 g, 0.04 mol) and Bu4N+Br− (1.5 g, 0.0046 mol) were added to a solution of crude compound (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(tert-butyloxycarbonyl)-3-isoquinolinecarboxylic acid (297 g, 0.8357 mol) in DMF (890 mL) at 20-25° C. The reaction mixture was stirred at 40-50° C. for 5 h. The reaction mixture then was cooled to 0-5° C., and water (1.78 L) was added in portions (IT<20° C.). The resulting light yellow suspension was stirred at 5-15° C. The mixture was filtered and washed with water (2×600 mL) and heptane (600 mL). The off-white solids were dried under vacuum at 45° C. to afford crude (S)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(tert-butyloxycarbonyl)-3-isoquinolinecarboxylic acid benzyl ester (335 g, 93.8% yield). 1H NMR (DMSO-d6) δ: 1.35, 1.45 (s, 9H, C(CH3)3), 2.93-3.18 (m, 2H, CH2CHCOOH), 3.17 (s, 6H, OCH3), 4.30 (d, J=16.15 Hz) and 4.37 (d, J=16.40 Hz, minor rotamer) (1H, CHHN), 4.45 (d, J=16.15 Hz) and 4.52 (d, J=16.40 Hz, minor rotamer) (1H, CHHN), 4.68 (dd, J=5.4, 4.3 Hz) and 4.90 (dd, J=5.9, 2.2 Hz, minor rotamer) (1H, CHCOOH), 6.74, 6.78, 6.81 (s, PhH).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[CH3:21]OC(OC)(C)C.CO.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:21][O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH:4]=[CH:3]2)[CH:11]=1
Reactant: COC(C)(C)OC
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(C)[C@H]1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC1=CC2=CC[C@H]3[C@@H]4CC=C[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Yield: 44.5 %

Procedure:
To a partial solution of androsta-4,16-dien-3-one (1.00 g, 3.70 mmol) in 2.2-dimethoxypropane (5.0 mL, 41 mmol) and 5 mL DMF were added methanol (0.2 mL) and p-toluenesulfonic acid monohydrate (26.4 mg, 0.139 mmol). The mixture was refluxed 5 h, after which it was cooled and sodium bicarbonate (152.5 mg) was added. The suspension was partitioned between 50 mL of ice water and 50 mL of ethyl acetate. The organic layer was washed with two 50 mL portions of water+50 mL of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residual oil was taken up in 50 mL of hot hexane and filtered through a 12 mm×30 mm column of silica gel 60 using 150 mL of hot hexane. The combined filtrates were concentrated under reduced pressure and recrystallized from acetone/methanol to give white crystals (468.0 mg, 1.645 mmol, 44%), m.p. 83-92° C.
Reaction SMILES: [C:1]([OH:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:17][CH2:18][CH2:19][C@H:20]1[CH2:24][N:23]([CH3:25])[C@H:22]([C:26]([NH:28][C@H:29]([C@H:41]([OH:43])[CH3:42])[C@H:30]2[O:35][C@H:34]([S:36][CH3:37])[C@H:33]([OH:38])[C@@H:32]([OH:39])[C@H:31]2[OH:40])=[O:27])[CH2:21]1.Cl>O>[CH3:17][CH2:18][CH2:19][C@H:20]1[CH2:24][N:23]([CH3:25])[C@H:22]([C:26]([NH:28][C@H:29]([C@H:41]([OH:43])[CH3:42])[C@H:30]2[O:35][C@H:34]([S:36][CH3:37])[C@H:33]([OH:38])[C@@H:32]([OH:39])[C@H:31]2[OH:40])=[O:27])[CH2:21]1.[C:1]([O-:16])(=[O:15])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O-:14])=[O:13]
Reactant: O=C(O)/C=C/CCCCCCCCC(=O)O
Agent: CCC[C@@H]1C[C@@H](C(=O)N[C@@H]([C@H]2O[C@H](SC)[C@H](O)[C@@H](O)[C@H]2O)[C@@H](C)O)N(C)C1
Agent: Cl
Solvent: O
Product: O=C([O-])/C=C/CCCCCCCCC(=O)[O-]
Temperature: 4 °C

Procedure:
2.28 g of trans-traumatic acid (10 mmol) are suspended in 100 ml of water cooled to 4° C. A solution of 8.86 g of lincomycin hydrochloride (20 mmol) in 100 ml water is eluted through a column cooled to 4° C. containing 35 ml of [OH--] Dowex 1×8 resin. The eluate free from chlorides is collected in the form of a suspension of traumatic acid kept under continuous stirring at 4° C. The resulting solution is frozen and lyophilized. The reaction yield is 10.1 g of dry product.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9]([CH3:11])=[CH2:10])=[CH:3][CH:2]=1.C1COCC1.[Br:18]Br>>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7][CH2:8][CH:9]([CH3:11])[CH2:10][Br:18])=[CH:5][CH:6]=1
Reactant: C=C(C)CSc1ccc(C)cc1
Reactant: BrBr
Solvent: C1CCOC1
Product: Cc1ccc(SCC(C)CBr)cc1

Procedure:
3-p-Tolylthio-2-methylpropene (15 mmol, 2.67 g) was hydroborated with BH3 -THF (5 mmol) at 0°. The brominations were carried out as described in the general procedure. The product was isolated via chromatography; yield 2.67 g (61%); [90% via Br2 reactions]; m.s. 257 and 259 [M-1] (calcd. 258 and 260); NMR (CDCl3) δ 1.0 (d, 3H, --CH3), 1.6 (m, 1H, --CH--), 2.2 (s,2H, ArCH3), 3.4 (m, 2H, --CH2Br), 3.2 (d, 2H, --SCH2), 7.0 (A'2X'2, 4H, ArH).
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N:10]=O)=[C:5]([NH2:12])[N:4]=1.[C:13]([O:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].O>C(OCCO)C>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]2[C:5](=[N:12][C:22]([NH2:23])=[C:21]([C:20]3[CH:19]=[CH:18][C:17]([O:16][C:13](=[O:15])[CH3:14])=[CH:25][CH:24]=3)[N:10]=2)[N:4]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: CC(=O)Oc1ccc(CC#N)cc1
Agent: [Na]
Solvent: O
Solvent: CCOCCO
Product: CC(=O)Oc1ccc(-c2nc3c(N)nc(N)nc3nc2N)cc1
Reaction time: 2 h

Procedure:
410 mg of metallic sodium are dissolved with stirring in 100 ml of 2-ethoxy-ethanol. 1100 mg of 2,4,6-triaminonitroso-pyrimidine and 1140 mg of p-acetoxybenzyl-cyanide are added with stirring one after the other and the mixture is heated to the boiling point with stirring. The color of the mixture changes from violet to brown. After two hours' boiling under reflux, heating is discontinued and the reaction mixture is left to cool. Subsequently, 70 to 80 percent of the 2-ethoxy-ethanol are drawn off using the vacuum from a water aspirator and the residue is combined with 500 ml of water. After extraction four times with ether, the extract is adjusted to pH 5 with 2 N hydrochloric acid. The precipitate is filtered off, washed with a little ice-cold acetone and recrystallized from 10 percent acetic acid. Further purification can follow using a silica gel column. The compound mentioned in the title is obtained, which compound decomposes (with charring) at 319°-321° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C@H:11]([O:13]C1CCCCO1)[CH3:12])=[CH2:10].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[CH2:10])[C@H:11]([OH:13])[CH3:12]
Reactant: C=C(c1ccc(F)cc1F)[C@@H](C)OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C=C(c1ccc(F)cc1F)[C@@H](C)O
Temperature: 60 °C

Procedure:
A mixture of crude 5b, and pyridinium-p-toluenesulfonate (35 g, 0.14 mole) in ethanol (1.2 L) is heated at 60° C. for 9 hours. The reaction mixture is concentrated in vacuo and co-evaporated with toluene. The residue is diluted with toluene and the resulting solid is removed by filtration. The filtrate is evaporated under reduced pressure to give the crude 6b as light brown oil.
Reaction SMILES: [CH3:1][C:2]([CH3:19])=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:6]1.[CH:20]([NH:23][NH:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:20]([N:23]([C:16](=[O:18])/[CH:15]=[CH:14]/[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:3]=[C:2]([CH3:1])[CH3:19])[CH:6]=1)[NH:24][C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:22])[CH3:21]
Reactant: CC(C)=CCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: Cc1ccc(C(=O)NNC(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCn1cc(/C=C/C(=O)N(NC(=O)c2ccc(C)cc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acrylic acid (100.0 mg, 0.39 mmol), N′-isopropyl-4-methylbenzohydrazide (113.4 mg, 0.59 mmol) and HATU (224.3 mg, 0.59 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.10 ml, 0.59 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (35% EtOAc) for refinement and dried so that white (E)-N′-isopropyl-4-methyl-N′-(3-(1-(3-methylbut-2-enyl)-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (74.0 mg, 44.1%).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9]([F:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[N:6][N:7]=1)[CH3:2].CCN=C=NCCCN(C)C.Cl.Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9]([F:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:45]=[CH:44][C:41]([C:42]#[N:43])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[O:15])=[N:6][N:7]=1)[CH3:2]
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2F)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2F)[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a round-bottom flask was added a solution of 5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid (compound 258.1, 125 mg, 0.500 mmol, 1.00 equiv) in DMF (10 mL). EDC.HCl (143 mg, 0.750 mmol, 1.50 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 122 mg, 0.550 mmol, 1.10 equiv), and 4-dimethylaminopyridine (183 mg, 1.50 mmol, 3.00 equiv) were added in portions. The resulting solution was stirred for 1 h at 40° C. in an oil bath, then quenched with 50 mL of NH4Cl (aq.sat.). The mixture was extracted with 40 mL of ethyl acetate and the combined organic layers were washed with 3×30 mL of NH4Cl (aq.sat.), dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 180 mg (86%) of 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:25])=[CH:8][CH:7]=2.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.N1C=CC=CC=1.[Cl:60][C:61]1[CH:62]=[C:63]([CH2:68][S:69](Cl)(=[O:71])=[O:70])[CH:64]=[CH:65][C:66]=1[Cl:67].Cl>ClCCl.CCCCCCC.C1(C)C=CC=CC=1.O>[CH:26]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:25])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:69]([CH2:68][C:63]1[CH:64]=[CH:65][C:66]([Cl:67])=[C:61]([Cl:60])[CH:62]=1)(=[O:71])=[O:70])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCCc1c(CCCc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: Cl
Solvent: CCCCCCC
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccc(CCCc2c(CCNS(=O)(=O)Cc3ccc(Cl)c(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 35 °C
Yield: 70.1 %

Procedure:
To a suspension of 4-{3-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid (125.0 g, 0.239 mol) in dichloromethane (1.25 L) at ambient temperature, bis(trimethylsilyl)trifluoroacetamide (89.2 g, 0.347 mol) was added. After refluxing for 0.5 hours, the reaction mixture was cooled to 35° C. To the reaction mixture solution, pyridine (49.1 g, 0.621 mol) and a solution of (3,4-Dichloro-phenyl)-methanesulfonyl chloride (68.2 g, 0.263 mol) in dichloromethane (200 mL) were added successively. The reaction mixture was refluxed for 0.5 h and then cooled to room temperature. Water (1.25 L) and conc.HCl (61.6 g) were added to the reaction mixture successively. The organic layer was washed with water (600 mL×2) and concentrated. The concentrate was dissolved in 2-propanol (710 mL) added to cold water (2.45 L) and the crude product (173.0 g, yield 97%, HPLC 78%, SLI 11%) was collected after filtration. Pure 4-(3-{1-Benzhydryl-5-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid (WAY-195902, 125.0 g, yield 72%, HPLC 98%, SLI 033%) was obtained by successive treatment of the crude product with a mixture of toluene and heptane followed by a mixture of ethyl acetate and heptane. 1H NMR (DMSO−d6): δ12.80 (br.s, 1H), 7.89 (d, 2H, J=2 Hz), 7.59 (d, 1H, J=1.5 Hz), 7.53 (d,1H, J=6 Hz), 7.48 (d, 1H, J=1.5 Hz), 7.38 (m, 9H), 7.20 (m, 5H), 6.77 (dd, 1H, J=6.9 & 1.5 Hz), 6.46 (d, 1H, J=6.9 Hz), 4.36 (s, 2H), 3.18 (m,2H), 2.96 (m,2H), 2.76 (m, 4H), 1.90(m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH:16]([C@@H:18]1[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][N:20]([C@H:29]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:30]([O:32]CC2C=CC(OC)=CC=2)=[O:31])[CH2:19]1)=O>>[CH:9]1[N:8]=[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:16][C@@H:18]3[C@@H:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:21][N:20]([C@H:29]([CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[C:30]([OH:32])=[O:31])[CH2:19]3)[CH2:6][CH2:5]2)[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=12
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccn2c(C3CCNCC3)ncc2c1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(c3ncc4ccccn34)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 3-(piperidin-4-yl)imidazo[1,5-a]pyridine (from Step B) and 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, (4-methoxy)benzyl ester (Aldehyde 5) using procedures analogous to those described in Example 95 (Steps C and D). ESI-MS 501 (M+1); HPLC A: 1.20 min.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:32]>CN(C)C=O>[CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH3:32])[C:9](=[O:17])[CH:8]([NH:18][C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: O=C(NC1N=C(C2CCCC2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Yield: 77.7 %

Procedure:
To a solution of 5-cyclopentyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (1.47 g, 3.91 mmol) in anhydrous dimethylformamide (40 ml) under nitrogen, cooled in an ice bath, was added sodium hydride (55% dispersion in oil, 178 mg, 4.08 mmol) in portions and the resulting mixture stirred for lb. Iodomethane (0.26 ml, 4.1 mmol) was then added and the mixture stirred for 30 min. The solvent was evaporated and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The aqueous layer was re-extracted with dichloromethane (20 ml), the organic extracts were combined, dried (MgSO4), and evaporated. The residue was triturated with diethyl ether to afford the title compound (1.19 g, 78%) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.26 (1H, m), 1.46-2.00 (6H, m), 2.00-2.20 (1H, m), 3.30 (1H, m), 3.40 (3H, s), 5.08 (2H, d, J=1.4 Hz), 5.15 (1H, d, J=8 Hz.), 6.50 (1H, d, J=8 Hz), 7.24-7.62 (9H, m).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[NH4+].[Cl-].O>CN(C=O)C>[N:2]1[NH:15][N:16]=[N:17][C:1]=1[C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)COc1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2nn[nH]n2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution methyl 2-(4-cyanophenoxy)acetate in DMF was treated with NaN3 and NH4Cl and stirred in an oil bath at 80° C. for 18 hours. Then, the mixture was poured into H2O and extracted with Et2O. The aqueous layer was acidified to pH 2-3 with HCl and the precipitate was collected to give methyl 2-(4-(2H-tetrazol-5-yl)phenoxy)acetate.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O.C([Si](C)(C)[O:27][C@H:28]1[CH2:37][CH2:36][CH2:35][C@@:34]2([CH3:38])[C@H:29]1[CH2:30][CH2:31][CH2:32][C@@H:33]2[C@H:39]([CH3:47])[CH2:40][C:41]#[C:42][C:43]([CH3:46])([OH:45])[CH3:44])(C)(C)C>C1COCC1>[OH:45][C:43]([CH3:44])([CH3:46])[C:42]#[C:41][CH2:40][C@H:39]([C@H:33]1[CH2:32][CH2:31][CH2:30][C@@H:29]2[C@:34]1([CH3:38])[CH2:35][CH2:36][CH2:37][C@@H:28]2[OH:27])[CH3:47]
Reactant: C[C@H](CC#CC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CC#CC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
12.0 g (38.0 mmol) of nBu4NF.3H2O in 40 ml of THF was carefully dried by stirring during 2 h at RT over 15 g of 3 Å molecular sieve. This solution was then added to 1.93 g (4.748 mmol) of (R)-6-[(1R,4aR,5S,8aR)-5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-2-methyl-hept-3-yn-2-ol and the mixture kept for 40 h at 55°. The reaction mixture was then poured onto crushed ice, extracted twice with ether, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) afforded 1.22 g of the title compound as white crystals of mp. 134-135°.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O>[C:23]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(CO)(c2ccc(Cl)cc2)CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(c2ccc(Cl)cc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 66 %

Procedure:
The 4-hydroxymethyl-4-(4-chlorophenyl)cyclohexanone is dissolved in 60 ml. of pyridine and 30 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness to give 12.8 g. (66% yield) of 4-acetoxymethyl-4-(4-chlorophenyl)cyclohexanone, as an amorphous gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13]([O:20][CH2:21][CH2:22][OH:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:13]([O:20][CH2:21][CH2:22][O:23][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccnc(Br)c1
Reactant: OCCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccnc(OCCOCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-bromoisonicotinate (575 mg, MATRIX) in THF (25 ml) was added with ethylene glycol monobenzyl ether (710 μl, TCI), cooled to 0° C., and added with potassium t-butoxide (420 mg, TCI), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with purified water (15 ml), and extracted with ethyl acetate (30 ml×2). The organic layers were combined, washed with saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Flash, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate ii-01).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: CNC
Reactant: O=C1NCc2cc(F)ccc21
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CNC2=O
Temperature: 165 °C
Yield: 81 %

Procedure:
A 500-mL high-pressure bomb reactor was charged with 123b (2.20 g, 14.5 mmol) ethanol (30 mL) and excess dimethylamine (50 mL). The mixture was heated at 165° C. for 36h. After this time, the mixture was concentrated and the resulting residue was purified by flash column chromatography (silica, 98:2 ethyl acetate/triethyl-amine) to afford an 81% yield (2.40 g) of 123c as a yellow solid: mp 122-124° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.44 (d, 1H, J=9.3 Hz), 6.77 (m, 2H), 4.24 (s, 2H), 2.99 (s, 6H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10]>>[N+:9]([CH:12]([CH3:13])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccccc1
Product: CC(C(O)c1ccccc1)[N+](=O)[O-]

Procedure:
In a preferred embodiment, a method for producing 2-nitro-1-phenyl-1-propanol is provided. This method comprises reacting benzaldehyde with nitroethane in the presence of an amine catalyst. The 2-nitro-1-phenyl-1-propanol produced by this reaction has a (1R*,2S*) stereoisomer and a (1R*,2R*) stereoisomer. The preferred (1R*,2S*) stereoisomer makes up greater than about 50% of the 2-nitro-1-phenyl-1-propanol. Reduction of this nitro-alcohol produces dl-norephedrine in high yield.