Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@@:10]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)([OH:14])[CH2:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[NH4+].[Cl-]>C1COCC1>[Si:32]([O:31][CH2:30][CH2:29][O:14][C@:10]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]1)([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)[CH2:11][CH2:12][CH3:13])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCC[C@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@](OCCO[Si](C)(C)C(C)(C)C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.5 %

Procedure:
To a suspension of NaH (2.4 g, 60 mmol) in dry THF (20 mL) was added a solution of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (7.34 g, 20 mmol) in dry THF (80 mL) at 0° C. The reaction mixture was stirred at rt for 2 h. Then a solution of (2-bromoethoxy)(tert-butyl)dimethylsilane (14.3 g, 60 mmol) in THF (100 mL) was added dropwise. After addition, the resulting mixture was stirred under reflux overnight. To the reaction mixture was added dropwise saturated NH4Cl solution, extracted by EtOAc (2×100 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel to afford (R)-tert-butyl 3-((R)-1-(2-(tert-butyldimethylsilyloxy)ethoxy)-1-(3-chlorophenyl)butyl)piperidine-1-carboxylate (1.1 g, 10%). 1H NMR (CDCl3, 400 MHz) δ 7.35 (s, 1H), 7.22 (m, 3H), 4.05 (m, 2H), 3.81 (m, 2H), 3.31 (m, 2H), 2.42 (t, 3H), 2.06 (m, 3H), 1.85 (m, 2H), 1.58 (m, 2H), 1.44 (s, 9H), 1.41-1.01 (m, 7H), 0.92 (s, 9H), 0.095 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](O)=O)=[C:4]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[C:15]([CH3:24])[CH:14]=2)[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:6]1[C:5]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([F:11])[CH:9]=2)[N:12]=[C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:16]=[C:15]([CH3:24])[C:14]=12
Reactant: Cc1cc(Nc2cc(F)c(F)cc2C(=O)O)n(-c2ccccn2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(-c2ccccn2)c2nc3cc(F)c(F)cc3c(Cl)c12
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of 4,5-difluoro-2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (8.14 g, 24.6 mmol) in phosphorous oxychloride (13 mL, 138 mmol) was heated under reflux for 1.5 hours. The solution was cooled to room temperature and concentrated under reduced pressure, and the residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (4.42 g, 54% yield).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([N:17]=[C:18]=[S:19])[N:6]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>C(Cl)Cl>[F:21][C:2]([F:1])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])[N:8]=[C:7]([NH:17][C:18](=[S:19])[N:23]([CH3:22])[C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)[N:6]=1
Reactant: CNc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)COc1cc(OCC(F)(F)F)nc(N=C=S)n1
Solvent: ClCCl
Product: CN(C(=S)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a solution of 4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl isothiocyanate (6.87 mmol) in CH2Cl2 (10 mL) was added N-methyl-4-trifluoromethylaniline (6.87 mmol) and the resulting solution was stirred at room temperature. After 18 h the solvent was evaporated and the crude material purified by chromatography (silica, hexane/EtOAc) to afford 131 as a yellow solid (2.15 g, 62% yield): m.p. 109-111° C.; 1H NMR (CDCl3) δ 7.76 (d, 2H, J=8.5), 7.46 (d, 3H, J=8.5 Hz), 5.96 (s, 1H), 4.77-4.68 (q, 4H, J=8.5 Hz); ESI/MS 509 (M+H), 507 (M−H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])[N:4]([C:17](=[O:35])[C@@H:18]([NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:19])[C:3]1=[O:36]>[Pd]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[N:4]([C:17](=[O:35])[C@@H:18]([NH:20][C@H:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:19])[C:3]1=[O:36]
Reactant: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Product: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)O)C(=O)OCC
Yield: 93.1 %

Procedure:
1.95 g of benzyl (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 50 mg of palladium black are treated in the same manner as described in Example 1-(2), whereby 1.49 g of (4S)-1-methyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 93.1%
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH2:9]([C:2]1[NH:1][C:15](=[O:14])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCC(N)=CC(=O)OCC
Product: CCCc1[nH]c(=O)c(C(=O)OCC)cc1C(=O)OCC
Temperature: 20 °C

Procedure:
62.8 g (0.4 mol) of ethyl 3-amino-hex-2-en-oate and 86.4 g (0.4 mol) of diethyl ethoxymethylenemalonate are stirred at 100° C. for 40 hours. The mixture is cooled to 20° C. and the solid is filtered off with suction and recrystallised from ethanol.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([S:13](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:15])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][OH:25]>C1COCC1>[OH:25][NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][S:13]([N:10]1[CH2:9][CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:15])=[O:14]
Reactant: NO
Reactant: O=S(=O)(/C=C/c1ccccc1)N1CCN(c2ccccc2)CC1
Solvent: C1CCOC1
Product: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-phenyl-4-(trans-b-styrenesulfonyl)piperazine (108 mg) in THF (3 ml) was added hydroxylamine (0.45 ml, 50% aqueous solution). The mixture was stirred at ambient temperature for 18 hours. Solvent was removed in vauo and the residue dissolved in dichloromethane, washed with water, dried (Na2SO4) and evaporated to give the product 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-phenylpiperazine as a foam (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: C#CC(C)(C)O
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccc(F)cc2C1=O

Procedure:
3.57 g (10 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 6.5 hours with 0.925 g (11 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 165°-167°.
Reaction SMILES: [CH3:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].BrC1C=CC(C(C)(C)C(OCC)=O)=CC=1>>[CH3:8][C:2]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1nccs1
Agent: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)(C(=O)O)c1nccs1

Procedure:
The title compound was prepared according to the method of Example 22B substituting the product of Example 44D for the product of Example 22A.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11])=[N+]=[N-].[BH4-].[Na+]>CO>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: [N-]=[N+]=Nc1ccncc1S(N)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccncc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 55.2 %

Procedure:
4-Azido-pyridine-3-sulfonic acid amide (3.75 g, 18.83 mmol) was dissolved in methanol (80 mL). Sodium borohydride (0.712 g, 18.83 mmol) was carefully added portionwise. Vigorous effervescence was observed. The mixture continued to stir at 25° C. for 25 min. The mixture was concentrated in vacuo to a thick yellow sludge. The residue was dissolved in a mixture of ethyl acetate (200 mL) and saturated aqueous ammonium chloride solution (200 mL). The aqueous layer was back extracted with ethyl acetate (6×200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product, 4-amino-pyridine-3-sulfonic acid amide (1.8 g, 10.4 mmol, 55%), as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 6.63 (2H, bs), 6.68 (1H, d, J=5.4 Hz), 7.40 (2H, bs), 8.06 (1H, d, J=5.5 Hz), 8.43 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:25]1[CH2:29][CH2:28][CH:27]=[CH:26]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH:29]3[CH2:28][CH2:27][CH:26]=[CH:25]3)[C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: BrC1C=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1C1C=CCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3.25 g (10.16 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in DMF (150 mL) at 0° C. was added a dispersion of 60% sodium hydride in mineral oil (1.016 g, 25.4 mmol). Evolution of gas was observed. The cloudy reaction mixture was stirred at 0° C. for 20 min before adding 3-bromocyclopent-1-ene (4.48 g, 30.5 mmol). The cloudy reaction mixture warmed to room temperature and stirred at room temperature for 18 h. The reaction was quenched with sat. aq. NH4Cl solution, diluted with EtOAc and the layers were separated. The organic layer was washed with 1M LiCl, sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 25 to 100% EtOAc in hexanes) to give the title compound as a 5:2 mixture of diastereomers.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:28][CH2:29][C@@H:30]1[O:35][C:34](=[O:36])[C:33]2=[N:37][CH:38]=[CH:39][N:32]2[CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl.CO>[Si:11]([O:28][CH2:29][C@H:30]([OH:35])[CH2:31][N:32]1[CH:39]=[CH:38][N:37]=[C:33]1[CH2:34][OH:36])([C:24]([CH3:26])([CH3:27])[CH3:25])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](OC[C@H]1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H](O)Cn1ccnc1CO)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Add diisobutylaluminum hydride (1M in hexanes; 21.65 mL; 1.6 equiv; 21.65 mmoles) to a 0° C. solution of (6R)-6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (5.5 g; 1.0 equiv; 13.53 mmoles) in dichloromethane (130 mL). Stir the solution for 15 minutes, then add methanol (100 mL). After 5 minutes, add sodium borohydride (0.307 g; 0.6 equiv; 8.12 mmoles) and maintain the solution at 0° C. for 15 minutes. Add saturated sodium potassium tartrate solution (80 mL) and stir the solution at ambient temperature for 14 hours. Filter the solution and separate the liquid layers. Further extract the aqueous layer with dichloromethane (3×). Wash the combined organic extracts with 50% saturated brine, dry over magnesium sulfate, filter, and concentrate to afford the desired (2R)-1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol (5.30 g; 95%). MS (m/z): 411 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH:25]1([NH:28][CH2:29][C@@H:30]2[C@H:34]([F:35])[CH2:33][NH:32][CH2:31]2)[CH2:27][CH2:26]1>>[CH:25]1([NH:28][CH2:29][C@@H:30]2[C@H:34]([F:35])[CH2:33][N:32]([C:11]3[CH:10]=[C:9]4[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]4[C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])=[CH:3][C:2]=3[F:1])[CH2:31]2)[CH2:27][CH2:26]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 65 %

Procedure:
Using 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (337 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (174 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow powder (309 mg).
Reaction SMILES: [C:1]([NH:6][CH2:7][CH2:8][NH2:9])([O:3][CH2:4][CH3:5])=[O:2].[C:10]1([CH2:16][CH2:17][CH2:18]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([NH:6][CH2:7][CH2:8][NH:9][CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)NCCN
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)NCCNCCCc1ccccc1
Yield: 36 %

Procedure:
A solution of 0.88 g of carboethoxyethylenediamine, 1.33 g of 3-phenylpropyl bromide and 1.0 g of anhydrous potassium carbonate in 10 ml of tetrahydrofuran was heated overnight under reflux. The insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to alumina column chromatography (25 g). Elution with hexane-ethyl acetate (3:1 v/v) gave 0.54 g of N-carboethoxy-N,,N,-bis(3-phenylpropyl)ethylenediamine (1) and 0.60 g of N-carboethoxy-N'-(3-phenylpropyl)ethylenediamine (2).
Reaction SMILES: [C:1]1(=[N:10]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CN=C1.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Ti+3]>[C:17]([NH:10][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1)(=[O:19])[CH3:18]
Reactant: ON=C1CCc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)NC1=CCc2ccccc21
Reaction time: 1 h
Yield: 61.3 %

Procedure:
1-Indanone oxime (2.33 g, 0.016 moles) and imidazole (78 mg) in acetonitrile (45 ml) cooled in ice, were treated with acetic anhydride (11 ml, 0.12 moles) and the mixture thus stirred for one hour. Titanium triacetate (17 g) was added, followed by more acetic anhydride (11 ml, 0.12 moles). The mixture was brought to reflux under nitrogen. After 2 hours the mixture was allowed to cool, poured into 1M sodium carbonate (250 ml) and stirred for 15 minutes. Three-fold extraction with ethyl acetate, drying (MgSO4) and evaporation left a brown oil which was reevaporated with toluene. The brown residue was subjected to flash chromatography on silica gel with ethyl acetate/hexane 1:2 v/v. The major component was obtained as a white solid (1.7 g) from the appropriate fractions and was recrystallized from ethyl acetate/hexane to give the title compound, mp 137-138° C. (1.45 g, 52.9%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH3:14][C:15](OC(C)=O)=[O:16].OS(O)(=O)=O>O>[C:15]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:16])[CH3:14]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1cc(O)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 60.1 %

Procedure:
To 3,5-dihydroxybenzoic acid (20 g, 129 mmol) was added NaOH (15.6 g, 390 mmol) in 100 mL water. After the mixture was cooled to 0° C., Ac2O (13.2 g, 129 mmol) was added. The solution was stirred for 40 min and then acidified with 10% H2SO4 at 0° C. The precipitate was filtered and washed with cold water. The crude product was recrystallized from water to give 3-acetoxy-5-hydroxybenzoic acid (15.2 g, 60%). Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.96 (s, 1H), 7.40 (dd, 1H, J=1.5 Hz), 7.26 (dd, 1H, J=1.5 Hz), 6.86 (t, 1H, 2.1H), 2.27 (s, 3H); HRMS (EI+) found 196.0380 M+, calcd 196.0372 for C9H8O6.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.[BH4-].[Na+]>C(Cl)Cl.CO>[C:18]([Si:21]([CH3:23])([CH3:22])[O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxyphenyl benzoate (9.0 mmol) was dissolved in CH2Cl2 (9 mL/mmol), TBDMS-Cl (1.5 eq., 13.5 mmol) and imidazole (2.0 eq., 18.0 mmol) were added and the mixture was stirred at r.t. overnight. The mixture was diluted with MeOH (4.5 mL/mmol), and NaBH4 (2.5 eq., 22.5 mmol) was added slowly over 5 min (attention: vigorous gas evolution). The mixture was concentrated by removing CH2Cl2 under reduced pressure and the suspension was heated to 65° C. for 15 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28](S(O)(=O)=O)=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.COC1(OC)CCCCCC1>C(Cl)Cl>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:25][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Agent: COC1(OC)CCCCCC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCC1
Yield: 557.9 %

Procedure:
A solution of the compound 8 (450 mg, 1.20 mmol) and p-toluenesulfonic acid hydrate (20.0 mg, 0.105 mmol) in a mixture of methylene chloride (1 mL) - toluene (0.1 mL) was concentrated under reduced pressure. The residue was dissolved in toluene (2 mL), to which was added 1,1-dimethoxycycloheptane (1.51 g, 12.0 mmol). The reaction mixture was heated under reflux over 1 hour and concentrated to a small quantity. A drop of triethylamine was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Hexane was added thereto, the mixture was filtered to remove the insoluble matter, and the filtrate was purified by chromatography on an alumina column (eluate: hexane - ethyl acetate (2:1)) to give the compound 10 (275 mg, 47%) as oil. Rf 0.64 (Al2O3 60, Type E, 2:1 hexane -EtOAc).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(CN)O.O>COCCO>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: NCCO
Solvent: O
Solvent: COCCO
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 112.5 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in a mixture of 2-methoxyethanol (13.0 g) and ethanolamine (1.3 g, 21.3 mmol, 1.65 equiv) and is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of ethanolamine (9.6 g, 157.2 mol, 12.2 equiv) and 2-methoxyethanol (0.8 g) and then the solution is added in portions to the thebaine mixture at such a rate that the batch temperature is maintained in the range 110 to 115° C. The reaction mixture is held at 110 to 114° C. for 1 hour then cooled to less than 20° C. after which water (24 g) is added to the mixture. The resulting slurry (pH 10.9) is stirred, further cooled to 0 to 5° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to constant weight to give 8,14-dihydrothebaine (3.84 g, 95.3% yield; 98.4 area % purity by HPLC).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:18]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:17][C@@H:16]2[CH3:33])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.C(Cl)Cl.[C:46](Cl)(=[O:48])[CH3:47]>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1)[C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]([N:25]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:46](=[O:48])[CH3:47])[CH2:17][C@@H:16]1[CH3:33])=[O:14]
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of (3,5-bis(trifluoromethyl)phenyl)((2S,4R)-4-(4-chlorophenylamino)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)methanone (19.44 g, 0.037 mol) in acetyl chloride (5 mL) was cooled to 0° C. and triethylamine (6.59 mL, 0.037 mol) was added dropwise over 30 min, a precipitate forms during this time. An additional 250 mL of methylene chloride was added to completely dissolve all the precipitate. The reaction was allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure, partitioned between ethyl acetate and 1N sodium hydroxide while cooled to 0° C. The aqueous layer was extracted 3 times with ethyl acetate washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-((2S,4R)-1-(3,5-bis(trifluoromethyl)benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-chlorophenyl)acetamide (H-31) (18.2 g, 86%).