Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C@H:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[CH3:27])=[CH:14][CH:13]=2)[C:10](=[O:28])[CH2:9][CH2:8]1>ClCCl>[CH3:27][CH:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:11]2[C:10](=[O:28])[CH2:9][CH2:8][C@H:7]2[CH2:6][NH:5][C:1](=[O:3])[CH3:2])=[CH:17][CH:16]=1
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)NC[C@@H]1CCC(=O)N1c1ccc(OCCCN2CCCC2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Acetyl chloride (0.51 ml, 0.72 mmol, 1.2 eq) is added to a cooled (ice bath) solution of (5S)-5-(aminomethyl)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 113 (0.2 g, 0.6 mmol, 1 eq) in dichloromethane (12 ml). The mixture is stirred 2 hours at room temperature, washed with a saturated solution of sodium bicarbonate and with brine, dried over magnesium sulfate and concentrated under vacuum to give 0.158 g of yellow oil. The crude material is purified by two chromatographies over silicagel (first one: gradient dichloromethane/methanol/ammonia 100:0:0 to 88:12:1.2; second one: dichloromethane/methanol/ammonia 80:20:2).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][C@H:25]2[NH2:28])=[CH:21][CH:20]=1.Cl.FC(F)(F)C1C=C2C(CC[C@H]2N)=CC=1>>[OH:1][C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]2[C:10]([C:11]=1[C:12]([NH:28][C@H:25]1[C:26]3[C:22](=[CH:21][CH:20]=[C:19]([C:18]([F:17])([F:29])[F:30])[CH:27]=3)[CH2:23][CH2:24]1)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: N[C@@H]1CCc2ccc(C(F)(F)F)cc21
Reactant: Cn1c(=O)c(O)c(C(=O)Cl)c2ccccc21
Agent: Cl
Product: Cn1c(=O)c(O)c(C(=O)N[C@@H]2CCc3ccc(C(F)(F)F)cc32)c2ccccc21
Yield: 20 %

Procedure:
Following the procedure described for Example 3, Example 192 (4 mg, 9.94 μmol, 20% yield) was prepared as an off-white powder by using 3-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl chloride (see Example 3C) and (R)-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-amine (Intermediate 15). LCMS=2.07 min, [M+1]=403.1 (Method A); Orthogonal HPLC (150×4.6 mm 3.5 μm, 254 nm): Sunfire {RT=9.47 min, 98%}; Xbridge {RT=8.63 min, 92%}. 1H NMR (500 MHz, MeOD) δ ppm 7.80 (1 H, s), 7.64 (1 H, d, J=8.3 Hz), 7.48-7.57 (3 H, m), 7.44 (1H, d, J=8.0 Hz), 7.31 (1 H, t, J=7.4 Hz), 5.76 (1 H, t, J=7.4 Hz), 3.81 (3 H, s), 3.08-3.18 (1 H, m), 2.98-3.06 (1 H, m), 2.67-2.74 (1 H, m), 2.05-2.13 (1 H, m).
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])[P:2](=[O:11])([O:7][CH:8]([CH3:10])[CH3:9])[O:3][CH:4]([CH3:6])[CH3:5].C=O.[CH2:24](NCC)C>CO>[C:1]([P:2](=[O:11])([O:7][CH:8]([CH3:9])[CH3:10])[O:3][CH:4]([CH3:6])[CH3:5])([P:12](=[O:21])([O:13][CH:14]([CH3:16])[CH3:15])[O:17][CH:18]([CH3:20])[CH3:19])=[CH2:24]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: CCNCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OC(C)C)OC(C)C)P(=O)(OC(C)C)OC(C)C
Yield: 24.3 %

Procedure:
11.95 g (34.7 mmol) of tetraisopropyl methylenebisphosphonate, 5.2 g (173.5 mmol) of paraformaldehyde and 2.54 g (34.7 mmol) of diethylamine are combined with the same reactants and at the same conditions as described above in Example I. This mixture is then refluxed for 117 hours. After the methanol has been eliminated as described above in Example I, 3.0 g of tetraisopropyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[NH:25][S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7])C.Cl>C(O)C>[CH3:31][CH:29]([S:26]([NH:25][C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=2)=[CH:15][CH:16]=1)(=[O:27])=[O:28])[CH3:30]
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reaction time: 24 h

Procedure:
Add NaOH 2M (1 ml) to a suspension of 4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-4-carboxylic acid ethyl ester (0.128 mmol) in ethanol (1 ml) and stir 24 h. Add 6N HCl until pH is approximately 1 and a white solid precipitates. Filter the solid to provide the title compound: MS (ES−): 400 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:22]3[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=3)[N:9]=[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Fc1cnc2c(Cc3ccccc3F)n[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
192 mg (approx. 0.517 mmol) of the compound from example 38A were dissolved in dimethylformamide (4 ml), then 34.5 mg (0.862 mmol) of sodium hydride (60% in mineral oil) were added and the mixture was stirred at RT for 30 min. Then 129 mg (0.744 mmol) of 6-chloro-3-nitropyridin-2-amine were added and the reaction mixture was stirred at RT for 1 h. The mixture was added to water, and the solids were filtered off, washed repeatedly with water and dried under high vacuum overnight. This gave 348 mg (85% purity, 84% of theory) of the title compound in solid form.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH:25]=O.N>>[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:25][N:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[O:9][C:8](=[O:13])[CH:7]=2)[CH2:16][CH2:17]1
Reactant: CCc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: Cc1ccc(C=O)cc1C
Agent: N
Product: CCc1ccc2oc(=O)cc(NC3CCN(Cc4ccc(C)c(C)c4)CC3)c2c1

Procedure:
Prepared from 6-Ethyl-4-(piperidin-4-ylamino)-chromen-2-one and 3,4-dimethylbenzaldehyde in a manner analogous to that described above. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.21 (m, 3H) 1.77 (m, 2H) 2.16 (m, 2H) 2.27 (m, 6H) 2.66 (m, 2H) 3.07 (m, 2H) 3.45 (m, 2H) 3.73 (m, 1H) 4.23 (m, 2H) 5.36 (m, 1H) 7.25 (m, 5H) 7.44 (m, 1H) 7.95 (m, 1H); MS (DCI/NH3) m/z 391 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:24]=[CH:23][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:24]=[CH:23][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=4)=[N:12][S:13](=[O:14])(=[O:15])[C:9]=3[CH:8]=2)[CH2:28][CH2:27][CH2:26]1
Reactant: C1CNC1
Reactant: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCCBr)cc21
Product: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCCN3CCC3)cc21

Procedure:
According to the method in example 9, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxide and azetidine were converted to yield 6-(4-Azetidin-1-yl-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxide as yellow solid, MS: 449 (MH+, 1Br).
Reaction SMILES: CC1C=CC=CC=1.[C:8]1([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]3[CH:22]=[CH:23][C:24]([C:26](OC)=[O:27])=[CH:25][C:16]=3[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O>[C:8]1([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]3[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:16]=3[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCn1c(-c2ccccc2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCn1c(-c2ccccc2)nc2cc(CO)ccc21
Reaction time: 1 h
Yield: 91 %

Procedure:
(a-4) To a stirred and cooled (ice-bath) solution of 103.9 parts of sodium dihydro-bis(2-methoxyethoxy)aluminate in 45 parts of methylbenzene was added dropwise a solution of 88.5 parts of methyl 2-phenyl-1-propyl-1H-benzimidazole-5-carboxylate in 270 parts of methylbenzene. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was decomposed by the addition of a mixture of 200 parts of a sodium hydroxide solution 7.5 N and 200 parts of water. The methylbenzene-phase was separated, dried, filtered and evaporated. The residue was washed with 210 parts of 2,2'-oxybispropane. The product was filtered off and dried, yielding 73 parts (91%) of 2-phenyl-1-propyl-1H-benzimidazole-5-methanol; mp. 112.9° C. (int. 60).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.Cl>C(Cl)Cl.C(OCC)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O

Procedure:
1 g of podophyllotoxin I is dissolved in a mixture of 15 ml of CH2Cl2 and 5 ml of ethyl ether. A slight stream of gaseous hydrochloric acid is introduced into the solution for 15 min at -10° C. and then stirring is maintained at this temperature for 1 h. After evaporating the reaction mixture without heating, 0.54 g of D,L-methionine and then 5 ml of methanesulfonic acid are added. After dissolving and stirring for 1 h with return to ordinary temperature, the reaction mixture is plunged into a water-acetone mixture and then BaCO3 is added to neutrality. After extracting with ethyl acetate, separating by settling, drying over Na2SO4, filtering and evaporating under reduced pressure, a residue is obtained which is crystallized from ethyl ether to provide 0.5 g (Yd 52%) of white crystals of 4'-demethylepipodophyllotoxin exhibiting a homogeneous spot by TLC.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Br:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([CH2:18][C:19]#[N:20])=[CH:15][CH:14]=[CH:13]2>CO>[OH:6][N:5]=[C:19]([NH2:20])[CH2:18][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[Br:7])[CH:13]=[CH:14][CH:15]=1
Reactant: N#CCc1cccc2cccc(Br)c12
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1cccc2cccc(Br)c12)=NO
Reaction time: 24 h
Yield: 62.2 %

Procedure:
A mixture of NaOMe (25 wt % in MeOH, 1.6 ml, 6.83 mmol), MeOH (3 mL), and hydroxylamine hydrochloride (0.47 g, 6.83 mmol) was heated for 30 minutes. 8-Bromo-2-naphthalenylacetonitrile (1.12 g, 4.55 mmol) and MeOH (5 mL) were added and heating was continued for 24 hours. The mixture was concentrated, and suspended in H2O (40 mL) and ether (2 mL). The off-white solid was collected by filtration and triturated with ether to give the title compound (790 mg, 62%), m.p. 123°-125° C.
Reaction SMILES: [Si]([C:8]1[O:9][C:10]2[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:11]=2[C:12]=1[C:13](=[O:26])[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23])[C:13]([C:12]1[C:11]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:10]=2[O:9][CH:8]=1)=[O:26]
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)coc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-benzofuran (30 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 μL, 0.076 mmol, 1M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (tlc), diluted with ethyl acetate (10 mL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent=hexane/diethyl ether; 7:3) to afford the title product as a creamy crystalline solid; (19.3 mg, 86%); 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 1H, J=8.97 Hz), 8.01 (s, 1H, C2H), 7.14 (s, 2H, benzoyl Hs), 7.05 (d, 1H, J=2.11 Hz), 7.00 (dd, 1H, J=8.63, 2.11 Hz), 3.93 (s, 3H, OMe), 3.90 (s, 6H, 2×OMe), 3.87 (s, 3H, OMe); 13C NMR (75 MHz, CDCl3) δ 188.71 (CO), 158.64, 156.31, 152.82, 150.22, 141.72, 133.97, 122.58, 120.87, 118.12, 113.11, 106.07, 95.53, 60.63, 55.99, 55.40.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[NH:9][NH2:10]>>[C:13]([O:12][C:8]([NH:9][N:10]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCOCC1
Product: CC(C)(C)OC(=O)NN=C1CCOCC1
Temperature: 67.5 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
Tetrahydro-4H-pyran-4-one (1.002 g, 10.01 mmol, CAS #29943-42-8, purchased from Fluka) was combined with tert-butyl carbazate (1.322 g, 10.00 mmol) in hexanes (10 mL). The mixture was heated in an oil bath at 65-70° C. for 75 minutes. A new precipitate began to precipitate out of solution before the carbazate completely went into solution. The mixture became very thick with the solid precipitate. Diluted with additional hexanes and heated another 15 minutes. The mixture was cooled to room temperature and concentrated in vacuo. Isopropanol was added to the residue and the mixture was stirred vigorously for 5 minutes and then diluted with ether and chilled. The solid was collected by filtration and dried in vacuo to give N′-(tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester 1.326 g, 62%). A second crop (0.373 g, 17%) was collected from the mother liquor.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:29])[NH:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][NH:25][CH2:26]3)=[CH:21][CH:20]=2)[CH:12]=1)=[O:8].CC(O)=O.[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH2:39]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([NH:18][C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][NH:9][C:7](=[O:8])[C:6]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:4]([O:3][CH3:2])[CH:5]=3)=[O:29])=[CH:20][CH:21]=2)[CH2:26]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(Cc3ccccc3)CC4)c2)cc1OC
Reaction time: 1 h

Procedure:
Suspended 3,4-Dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide hydrochloride (50.0 mg, 0.104 mmol) in 2 mL of THF. To this was added AcOH (0.06 mL, 1.0 mmol) and benzaldehyde (0.016 mL, 0.150 mmol). The mixture stirred for 1 h. To this was added NaBH(OAc)3 (63.3 mg, 0.300 mmol). The mixture stirred for 50 h. LC-MS analysis indicated the desired product. Concentrated the mixture to dryness. Redissolved in CH2Cl2/MeOH and applied to a SiO2 prep plate. Eluted with (10% MeOH/1% NH3/CH2Cl2) to give 40.6 mg of N-[3-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-3,4-dimethoxy-benzamide. MS, electrospray 536.4 (M+H).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(=O)C(Cl)=NNc1cccc(C)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C(=NNc1cccc(C)c1)Sc1ccc(Cl)cc1
Yield: 87.6 %

Procedure:
The reaction of 2.88 g (0.0136 mol)of 1-chloro-1-[(3-methylphenyl)hydrazono]-2-propanone with 2.10 g of 4-chlorothiophenol and 2.04 ml of triethyl amine in 35 ml of ethanol as Example 11 yielded 3.8 g of 1-[(4-chlorophenyl)thio]-1-[(3-methylphenyl)hydrazono]-2-propanone, mp 112°-114° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:18]([Cl:19])=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[Cl:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C:9]1[C:10]([Cl:20])=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][C:18]=1[Cl:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(CO)cc1Cl
Temperature: 25 °C
Yield: 25.9 %

Procedure:
To a stirred and cooled (0° C.) solution of 7.70 g (23.0 mmol) of the product of Step A dissolved in 50 mL of anhydrous THF was added 23.0 mL (23.0 mmol) of a 1M solution of lithium aluminum hydride in THF. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred 3.5 hours. The stirred reaction was then quenched by dropwise addition of 0.88 mL water, then 0.88 mL of 15% NaOH, and finally 2.62 mL water. The reaction mixture was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1N HC1, saturated NaHCO3, dried (MgSO4), and evaporated in vacuo to afford 1.83 g (26%) of the title compound.
Reaction SMILES: C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][Si](C(C)(C)C)(C)C)=[CH:40][CH:39]=2)[C:34](=[O:52])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:38]2[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=2)[C:34](=[O:52])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A THF solution (0.7 mL) of 1N tetrabutylammonium fluoride was added to a THF solution (2 mL) of 4-benzyloxy-1-{4-[tert-butyl(dimethyl)silyloxy]phenyl}-1H-pyridin-2-one (234 mg, 0.573 mmol) and stirred for 30 minutes at room temperature. Ethyl acetate was added to the reaction liquid, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the title compound (166 mg, 99%) was obtained.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][CH:7]=3.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[OH:1][C@@H:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)CCC1OC21
Reactant: C1CCNC1
Solvent: CCO
Product: O[C@@H]1CCc2ccccc2[C@H]1N1CCCC1

Procedure:
A mixture of 1,2-epoxy-1,2,3,4-tetrahydronaphthalene (19.8 g), pyrrolidine (15 ml) and ethanol (75 ml) was stirred at reflux for 2 hours and evaporated of the volatiles under reduced pressure. The residue was dissolved in ether and the solution was extracted with IN hydrochloric acid (200 ml). The acid extract was washed with ether and basified with 1N sodium hydroxide aqueous solution with cooling. The mixture was extracted with ether (2X) and the combined ether extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residual viscous liquid was distilled under vacuum to yield trans-1,2,3,4-tetrahydro-2-hydroxy-1-(pyrrolidin-1-yl)naphthalene (16.5 g), b.p. 128°-135°/0.25 torr.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([OH:1])[CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Product: CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1O

Procedure:
1-(2,4-Dihydroxy-phenyl)-ethanone was treated with 1 equivalent of benzyl 2-bromoacetate and processed as described in the synthesis of example 20a to obtain the title compound. The crude was purified using flash chromatography (silica gel, 3% CH3CN in chloroform) and crystallization was effected using ether-PE 60-80° C. Yield, 75%, white solid; mp, 66-67° C.; MS (EI): 300 (M+), 285, 165, 91 (100%); analysis: C17H16O5 requires C, 67.99; H, 5.37; found: C, 67.99; H, 5.53%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[SH-:13].[Na+]>CN(C=O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([SH:13])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: [SH-]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.7 %

Procedure:
1-Fluoro-4-(methylsulfonyl)-benzene (1.74 g) and sodium hydrosulphide hydrate (0.67 g) were dissolved in DMF (10 ml) and stirred at room temperature for 24 hours. The reaction was quenched with water, acidified with 2M hydrochloric acid (20 ml) and extracted with ethyl acetate (2×50 ml). The combined extracts were then washed with water (2×25 ml) and brine (20 ml). The organic solution was dried (MgSO4), filtered and evaporated in vacuo to yield the sub-title compound as a white solid (1.8 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].ON1C2C=CC=CC=2N=N1.[C:29]([NH:39][C@H:40]([C:45](O)=[O:46])[CH2:41][CH2:42][S:43][CH3:44])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH2:32]([O:31][C:29]([NH:39][C@@H:40]([CH2:41][CH2:42][S:43][CH3:44])[C:45]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:46])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO[C@@H]1CC[C@H](N)[C@H](CNC(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CO[C@@H]1CC[C@H](NC(=O)[C@H](CCSC)NC(=O)OCc2ccccc2)[C@H](CNC(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A sample of tert-butyl ((1S,2S,5R)-2-amino-5-methoxycyclohexyl)methylcarbamate (2.53 g, 9.79 mmol) was dissolved in CH2Cl2 (50 ml) at room temperature. The solution was charged sequentially with 1-hydroxybenzotriazole (1.456 g, 10.77 mmol), N-carbobenzyloxy-L-methionine (4.16 g, 14.69 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.440 g, 12.73 mmol). The reaction mixture was stirred overnight. It was diluted with EtOAc and washed with saturated Na2CO3, followed by brine. The solution was dried (MgSO4), filtered, and concentrated in vacuo to yield tert-butyl ((1S,2S,5R)-2-((S)-2-benzyloxycarbonylamino-4-(methylthio)butanamido)-5-methoxycyclohexyl)methylcarbamate as a colorless sticky solid. LC/MS found [M+H]+=524.31.