Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCC(C2C=CC=C(OCCCOC3CCCCO3)C=2)C(OCC2C=CC3C(=CC=CC=3)C=2)C1)C1C=CC=CC=1.ClC([O-])=O.[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[CH2:57][O:58][CH:59]1[CH:64]([C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([O:71][CH2:72][CH2:73][CH2:74][O:75]C3CCCCO3)[CH:66]=2)[CH2:63][CH2:62][N:61]([C:82]([O:84][CH2:85][C:86]([Cl:89])([Cl:88])[Cl:87])=[O:83])[CH2:60]1>>[OH:75][CH2:74][CH2:73][CH2:72][O:71][C:67]1[CH:66]=[C:65]([CH:64]2[CH2:63][CH2:62][N:61]([C:82]([O:84][CH2:85][C:86]([Cl:87])([Cl:88])[Cl:89])=[O:83])[CH2:60][CH:59]2[O:58][CH2:57][C:48]2[CH:49]=[CH:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:47]=2)[CH:70]=[CH:69][CH:68]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2cccc(OCCCOC3CCCCO3)c2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])Cl
Agent: c1ccc(CN2CCC(c3cccc(OCCCOC4CCCCO4)c3)C(OCc3ccc4ccccc4c3)C2)cc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2cccc(OCCCO)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 14, by alkylating (3RS,4RS)-1-benzyl-4-(3-hydroxy-phenyl)-piperidin-3-ol with rac.-2-(3-bromo-propoxy)-tetrahydro-pyran in the presence of potassium carbonate there was obtained a mixture of the diastereomeric racemates of (3RS,4RS)-1-benzyl-4-{3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-piperidin-3-ol as a colourless oil; Rf : 0.38 (hexane:acetone=1:1). Subsequent alkylation with 2-bromomethylnaphthalene analogously to Example 12(b) gave a mixture of the diastereomeric racemates of 1-benzyl-3-(naphthalen-2-ylmethoxy)-4-{3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-piperidine as a colourless oil; MS: 566 (M+H)+. Subsequent reaction with 2,2,2-trichloroethyl (sic) chloroformate analogously to Example 12(c) yielded a mixture of the diastereomeric racemates of 2,2,2-trichloroethyl 3-(naphthalen-2-ylmethoxy)-4-{3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-piperidine-1-carboxylate which, without further purification and characterization, was reacted with p-toluenesulphonic acid analogously to Example 53(c) to give 2,2,2-trichloroethyl (3RS,4RS)-4-[3-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate. Finally, by reaction with pyridine-2-carbonyl azide in an analogous manner to that described in Example 24(m) there was obtained 2,2,2-trichloroethyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{3-[3-(pyridin-2-ylcarbamoyloxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a colourless oil; Rf : 0.55 (methylene chloride:ethyl acetate=1:1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].S(Cl)SCl.S(Cl)(Cl)(=O)=O.[Cl:14]C1C=CC(C(Cl)(Cl)Cl)=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([C:33]([Cl:36])([Cl:35])[Cl:34])[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:14][C:29]1[CH:30]=[C:31]([Cl:32])[C:26]([Cl:25])=[CH:27][C:28]=1[C:33]([Cl:36])([Cl:34])[Cl:35]
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1Cl
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Agent: ClSSCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(=O)(Cl)Cl
Product: Clc1cc(Cl)c(C(Cl)(Cl)Cl)cc1Cl
Yield: 47 %

Procedure:
A solution of 4.6 g (34 mmol) of aluminum chloride and 4.6 g (34 mmol) of disulphur dichloride in 344 g (2.55 mol) of sulphuryl chloride was added dropwise to a mixture of 57.5 g (250 mmol) of p-chlorobenzotrichloride and 115 g (850 mmol) of sulphuryl chloride at 40° C. The reaction mixture was further processed in the manner described in Example 5, that is to say that, after the working up, unreacted p-chlorobenzotrichloride and 3,4-dichlorobenzotrichloride were separated off by distillation and fed to renewed chlorination with sulphuryl chloride under the conditions given here. By distillation of the combined sump fractions, 2,4,5-trichlorobenzotrichloride was obtained in a yield of 47% of theory.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:30]([O:37][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccccc1
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(NC(=O)c2ccc(OCc3ccccc3)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Temperature: 100 °C

Procedure:
4-Bromo-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2.4.AaBa, 1.00 g, 2.06 mmol) benzyl alcohol (3.1, 0.256 mL, 0.00247 mol) were dissolved in 10 mL dimethylformamide. The reaction was heated to 100° C. for 18 hours. Ethyl acetate (20 mL) was added and aqueous workup was performed. The organic layer was dried over magnesium sulfate evaporated and purified via SiO2 chromatography (16%-33% ethyl acetate/hexane) to yield 4-(benzyloxy)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2I) as a white solid. MS analysis (m+1)=513.7.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C@@:17]3([CH3:25])[CH2:21][CH2:20][N:19]([C:22]([O-:24])=[O:23])[CH2:18]3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:40][C:37]1[N:36]=[CH:35][C:34]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C@@:17]4([CH3:25])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:3]([CH3:16])([CH3:4])[CH3:2])=[O:23])[CH2:18]4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:39][N:38]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C[C@]1(N2CCc3c(Cl)nc(N4CCOCC4)nc32)CCN(C(=O)[O-])C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@](C)(N2CCc3c(-c4cnc(N)nc4)nc(N4CCOCC4)nc32)C1
Temperature: 120 °C
Yield: 803.2 %

Procedure:
Two separate reaction vessels containing a yellow mixture of (3S)-3-[4-chloro-2-(morpholin-4-yl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (prepared from 2-[4,6-dichloro-2-(morpholin-4-yl)pyrimidin-5-yl]ethanol (Preparation 1) and tert-butyl(3S)-3-amino-3-methylpyrrolidine-1-carboxylate (Preparation 4)) (3500 mg, 8.256 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (2.37 g, 10.7 mmol) and Na2CO3 (2630 mg, 24.8 mmol) in 1,4-dioxane (90 mL) and water (30 mL), were prepared. To each reaction mixture was added Pd(dppf)Cl2-DCM (362 mg, 0.495 mmol) in one portion at 15° C. under nitrogen atmosphere, and the reaction mixtures were heated at 120° C. for 16 h. The reaction mixtures were combined and concentrated to give 16 g of a black gum. The material was purified by silica gel column chromatography eluting with a gradient of 30-75% EtOAc in petroleum ether, followed by a gradient of 0-1% MeOH in EtOAc to give the title compound (7.0 g, 87%) as a yellow solid. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 8.73 (s, 2 H), 6.61 (br s, 2 H), 3.80-3.63 (m, 11 H), 3.54 (q, J=8.7 Hz, 1 H), 3.42-3.35 (m, 1 H), 3.33-3.25 (m, 1 H), 3.09 (t, J=8.2 Hz, 2 H), 2.44-2.35 (m, 1 H), 2.07-2.00 (m, 1 H), 1.42 (s, 9 H), 1.32 (s, 3 H). m/z (APCI+) for C24H34N8O3 483.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.C[N:26](C=O)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([NH2:26])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(Br)cc32)n1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid (500 mg, 1.32 mmol) in DCM (5 mL), was added thionyl chloride (0.6 mL, 7.9 mmol) followed by DMF (0.02 mL). The mixture was stirred at RT for 1 hr. The mixture was concentrated in vacuo, DCM (2 mL) added and concentration in vacuo was repeated. To this residue was added THF (5 mL) and conc. aq NH3 (0.5 mL). The mixture stirred for 30 min, then diluted with water and the resultant solid was collected by suction filtration. The solid was thoroughly dried under high vacuum, to give the title compound (360 mg): 1H NMR (250 MHz, DMSO) delta 7.15 (1H, br. s.), 7.32 (1H, d, J=5.48 Hz), 7.60 (1H, dd, J=8.60, 1.60 Hz), 7.74 (1H, br. s.), 8.20 (1H, d, J=8.38 Hz), 8.38 (1H, d, J=5.48 Hz), 9.18 (1H, d, J=1.22 Hz); LC-MS: m/z=+332.90/334.70 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[O:18]C)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:7][C:6]=1[OH:18])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxy-6-methyl-4-morpholin-4-yl-benzoic acid ethyl ester (7.0 g, 25.1 mmol) in dichloromethane (370 ml) is added neat boron tribromide (5.94 ml, 62.7 mmol) at −78° C. The temperature is slowly raised to room temperature over a period of 30 min and stirred for 1 h at room temperature. The reaction mixture is poured onto cold water, extracted with dichloromethane (3×30 ml). Combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude material is used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=C(Cl)[N:15]=1>>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH3:23])=[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:15]=1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: O=CNc1ccc([N+](=O)[O-])cc1
Product: Cn1cnc2c(Nc3ccc([N+](=O)[O-])cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-nitro-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].O>C(O)CCC>[CH3:15][O:16][CH2:17][CH2:18][NH:19][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COCCN
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Solvent: CCCCO
Solvent: O
Product: COCCNc1nnc(-c2ccccc2)cc1C

Procedure:
A mixture of 7 g of 3-chloro 4-methyl 6-phenyl pyridazine and 7 g of 2-methoxy ethylamine in 50 ml of butanol is taken to reflux for 4 days. The hot solution is poured into 200 ml of water and extracted with ethyl acetate. The organic solution is dried over magnesium sulfate then evaporated to dryness.
Reaction SMILES: [C:1]1([C@@H:7]2[C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[C@H:8]2[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>>[C:1]1([C@@H:7]2[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[C@H:8]2[C:14]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:26])[F:27])=[CH:20][CH:21]=2)=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)[C@H]1[C@H](c2ccccc2)C12CCCC2
Product: O=C(Nc1ccc(C(F)(F)F)cc1)[C@H]1[C@H](c2ccccc2)C12CCCC2
Yield: 60.1 %

Procedure:
trans-2-Phenylspiro[2.4]heptane-1-carboxylic acid (300 mg, 1.39 mmol) and 4-trifluoromethyl-phenylamine (224 mg, 1.39 mmol) were reacted as described under General Procedure D to furnish the title compound (300 mg, 60%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J=8.8 Hz, 2H), 7.58-7.52 (m, 3H), 7.33-7.20 (m, 3H), 7.15-7.12 (m, 2H), 2.92 (d, J=5.5 Hz, 1H), 2.06 (d, J=5.5 Hz, 1H), 1.93-1.91 (m, 2H), 1.73-1.60 (m, 4H), 1.52-1.40 (m, 2H). mp 171-173° C. ESIMS m/z [M+H]+ 360.2.
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:56]2[N:57]=[C:58]([NH:61]C(OC(C)(C)C)=O)[S:59][CH:60]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]([CH2:41][NH:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][NH:47]C(OC(C)(C)C)=O)[CH:38]=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][CH2:44][C:43]([NH:42][CH2:41][C:39]1[CH:38]=[N:37][N:36]([CH2:35][C@@H:27]2[C@H:26]([NH:25][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([OH:16])=[O:14])[CH2:19][CH2:18]3)/[C:56]3[N:57]=[C:58]([NH2:61])[S:59][CH:60]=3)[C:29](=[O:30])[N:28]2[S:31]([OH:34])(=[O:32])=[O:33])[N:40]=1)=[O:55]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-((4-((tert-butoxycarbonyl)amino)butanamido)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (47 mg, 48 μmol), DCM (0.5 mL), and TFA (0.2 mL, 2.87 mmol) for 2 h. The reaction mixture was concentrated in vacuo, and the residued was partitioned between DCM and ice water. The water layer was purified by reverse phase prep HPLC (XSelect CSH, 30×100 mm, 5 μm, C18 column; AcN-water with 0.1% formic acid modifier, 60 mL/min) affording the title compound LCMS: Rt=0.53 min, m/z=615.3 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O): δ 7.63 (s, 1H), 7.05 (s, 1H), 5.58-5.49 (m, 1H), 4.96-4.83 (m, 3H), 4.41 (br s, 2H), 3.06-2.90 (m, 2H), 2.44-2.28 (m, 2H), 1.98-1.83 (m, 2H), 1.38-1.04 (m, 4H).
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)#[CH:23]>>[O:11]=[C:9]1[CH2:8][C:7]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])=[N:6][C:5]2[CH:20]=[CH:21][C:2]([C:23]#[C:22][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[CH:3][C:4]=2[NH:10]1
Reactant: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Reactant: C#Cc1cccs1
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4cccs4)cc3NC(=O)C2)c1
Yield: 82.8 %

Procedure:
Prepared from 3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 50) (185 mg, 0.48 mmol) and 2-ethynylthiophene (78 mg, 0.72 mmol) [prepared from 2-thiophenecarboxaldehyde according to J. Org. Chem. 1982, 47, 2201-2204] according to the general procedure F. Obtained as a light yellow solid (146 mg).
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:14]([CH:23]([OH:31])[CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:13]C1(C)C)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:15]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH:14]([OH:13])[CH:23]([OH:31])[CH2:24][N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC1(C)OC(C(O)CN2CCCCC2)[C@H](CC2CCCCC2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H](CC1CCCCC1)C(O)C(O)CN1CCCCC1
Yield: 93.1 %

Procedure:
71 mg of (4S,5RS)-3-benzyloxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2piperidinoethyl]oxazolidine was dissolved in 1.5 ml of ethanol, and palladium black was added thereto. Then, hydrogenation was conducted at room temperature under atmospheric pressure. The catalyst was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain 41 mg of (2RS,3RS,4S)-4-amino-5-cyclohexyl-1-piperidino-2,3-pentanediol as colorless oily substance.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:34])[C:6]([CH3:33])=[C:7]([CH3:32])[C:8](=[O:31])[C:9]=1[CH2:10][CH2:11][C@@:12]([OH:30])([CH3:29])[CH2:13][CH2:14][CH2:15][C@H:16]([CH3:28])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:2]=[CH2:3].CCOC(C)=O>C(Cl)Cl.O=[Pt]=O>[OH:30][C@:12]([CH3:29])([CH2:13][CH2:14][CH2:15][C@H:16]([CH3:28])[CH2:17][CH2:18][CH2:19][C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11][CH2:10][C:9]1[C:8](=[O:31])[C:7]([CH3:32])=[C:6]([CH3:33])[C:5](=[O:34])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=C(C)C1=O
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCC1=C(CC[C@](C)(O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)C(=O)C(C)=C(C)C1=O
Reaction time: 120 h
Yield: 80 %

Procedure:
(R,R,R)-2-allyl-3-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5,6-dimethyl-[1,4]benzoquinone (Ex-1D-4) (50 mg, 0.1 mmol) was hydrogenated using PtO2 (5 mg) at 50 psi for 2 h in a solution of EtOAc (5 mL). The suspension was filtered through celite, which was rinsed with DCM (2×2 mL). The pale yellow solution was concentrated by rotary evaporation to yield a pale yellow oil (Ex-1D-5). The oil was dissolved in DCM (5 mL) and stirred with silica (˜20 mg) for 5 days. The bright yellow suspension was filtered through a cotton plug and concentrated by rotary evaporation to yield (R,R,R)-2-(3-hydroxy-3,7,11,15-tetramethyl-hexadecyl)-5,6-dimethyl-3-propyl-[1,4]benzoquinone (Ex-1D-6) as a bright yellow oil (38 mg, 76%). 1H NMR (400 MHz, CDCl3) δ (ppm): 2.57-2.52 (m, 2H), 2.48-2.44 (m, 2H), 2.02 (s, 6H), 1.57-1.04 (m, 26H), 0.99 (t, J=7.4 Hz, 3H), 0.89-0.85 (m, 15H).
Reaction SMILES: [OH:1][C:2]1([CH2:25][OH:26])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C=O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[CH2:25][O:26][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CO)CC3)cc2)C(=O)O1
Agent: C=O
Solvent: c1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)COCO4)cc2)C(=O)O1
Yield: 57 %

Procedure:
A mixture of (S)—N-{3-[4-(4-hydroxy-4-hydroxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.209 mmol), paraformaldehyde (0.233 mmol), p-toluene sulfonic acid (0.248 mmol), 4° A molecular sieves (0.160 g) in benzene (20 ml) was heated at reflux for 2 to 3 hours under stirring. The solvent was removed under vacuum to provide a residue. The residue was extracted with ethyl acetate water mixture. The combined organic layer was dried and concentrated to afford a crude product. The silica gel column chromatography afforded title compound in 57% yield.
Reaction SMILES: Br.BrC1C=CC(CCN)=CC=1.C(OCC)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][CH:27]=O)=[CH:20][CH:19]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Br:17][C:18]1[CH:23]=[C:22]2[C:21]([CH2:24][CH2:25][N:26]=[CH:27]2)=[CH:20][CH:19]=1
Reactant: O=CNCCc1ccc(Br)cc1
Agent: Br
Agent: NCCc1ccc(Br)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC=O
Product: Brc1ccc2c(c1)C=NCC2

Procedure:
The compound of formula II can be made as outlined in Scheme I and as specifically exemplified in Example 1. Referring to Scheme I, 2-(4-bromophenyl)ethylamine hydrobromide is reacted with ethyl formate in the presence of a base to make N-[2-(4-bromophenyl)ethyl]formamide. The fornamide is then treated with phosphorus pentoxide in polyphosphoric acid to cyclize, followed by treatment with hydrogen halide (e.g., HCl) gas to form the hydrohalide salt of 7-bromo-3,4-dihydroisoquinoline hydrohalide. The hydrohalide salt is then reduced to afford 7-bromo-1,2,3,4-tetrahydroisoquinoline. The reduced material is then nitrated by treatment with potassium nitrate in concentrated sulfuric acid and the appropriate fraction separated to yield 7-bromo6-nitro-1,2,3,4-tetrahydroisoquinoline. The nitrated material is then reacted with di-tert-butyl dicarbonate in the presence of a base to block the ring tetrahydroisoquinoline nitrogen, thereby affording 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. The ester is then hydrogenated in the presence of palladium-on-calcium carbonate to form the corresponding 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ester. The amine is then reacted with 4'-trifluoromethylbiphenyl-2-carboxylic acid to form 6-[4'-trifluoromethylbiphenyl-2-carbonyl)amino]3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester. This product can then be deblocked conventionally to make compound II, 4'-trifluoromethylbiphenyl-2-carboxylic acid (1,2,3,4tetrahydroisoquinolin-6-yl)amide. ##STR6##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[C:5]([CH3:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].C(OC(=O)[C@H:18](C)[NH2:19])C.C(OCC)=O.C(OC1OC=NC=1C)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(#N)C=C>S(=O)(=O)(O)O>[OH:9][C:4]1[C:5]([CH3:8])=[N:6][CH:7]=[C:2]([CH:3]=1)[C:18]#[N:19]
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cc1ncc(Br)cc1O
Agent: CCOc1ocnc1C
Agent: O=N[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C=CC#N
Solvent: CCOC=O
Product: Cc1ncc(C#N)cc1O

Procedure:
The 5-bromo-2-methyl-3-pyridinol, required for the syntheses of the brominated dihydrofuro- and dihydropyranopyridines, is produced by standard transformations of commercially available materials. Thus, 2-methylnicotinic acid (Aldrich Chemical Company) can be converted by sequential treatment with thionyl chloride, bromine, and ammonia, as described by Greco et al., J. Het. Chem. 7: 761 (1970), into 5-bromo-2-methylnicotinamide. Hofmann rearrangement of 5-bromo-2-methylnicotinamide with hypochlorite will give 3-amino-5-bromo-2-methylpyridine, which can be converted to 5-bromo-2-methyl-3-pyridinol by diazotization with sodium nitrite in aqueous sulfuric acid. Alternatively, alanine ethyl ester (Aldrich Chemical Company) is converted (using ethyl formate) into its N-formyl derivative, which is then converted to 5-ethoxy-4-methyloxazole using phosphorous pentoxide (see Takeo et al., Japan Patent No. 45,012,732). A Diels-Alder reaction of 5-ethoxy-4-methyloxazole with acrylonitrile gives 5-hydroxy-6-methylnicotinonitrile, as described by Yoshikawa et al., Chem. Pharm. Bull. 13: 873 (1965), which is converted to 5-amino-2-methyl-3-pyridinol by hydration (nitrileamide) and Hofmann rearrangement (see Morisawa et al., Agr. Biol. Chem. 39: 1275 (1975)). The 5-amino-2-methyl-3-pyridinol can then be converted, by diazotization in the presence of copper (I) bromide, to the desired 5-bromo-2-methyl-3-pyridinol.
Reaction SMILES: [C:1]([C:5]1[C:19]([O:20]CC=C)=[CH:18][C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:3])[CH3:2].CN(C)[C:26]1[CH:31]=CC=C[CH:27]=1>>[C:1]([C:5]1[C:19]([OH:20])=[C:18]([CH2:31][CH:26]=[CH2:27])[C:8]2[CH2:9][C:10]3([O:17][C:7]=2[CH:6]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Reactant: CN(C)c1ccccc1
Product: C=CCc1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Yield: 67 %

Procedure:
Under a nitrogen stream, a solution of 0.76 g of 6-t-butyl-5-(2-propenyloxy)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane was dissolved in 3 ml of dimethylaniline and the solution was refluxed overnight. The reaction mixture was allowed to attain room temperature and concentrated under reduced pressure, then extracted with ethyl acetate and 5% hydrochloric acid and the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1%-2% ethyl acetate) to give 0.51 g of 6-t-butyl-5-hydroxy-4-(2-propenyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (yield 67%).