Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4][NH:3][CH2:2]1.C(N(CC)CC)C.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.C1COCC1>[CH2:27]([N:3]1[CH2:2][CH2:1][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:4]1)[C:23]1[O:22][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Reactant: O=C(Cl)c1ccco1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1coc(CN2CC[C@H]3c4ccccc4CC[C@@H]3C2)c1
Yield: 37.9 %

Procedure:
Following the procedure of Example 16, 0.168 g (0.897 mmol) of trans-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline in 8 ml of anhydrous dichloromethane was reacted with 0.313 ml (2.25 mmol) of triethylamine and 0.177 ml (1.80 mmol) of 2-furoyl chloride for 11/2 h, then with 2.7 ml of a 1.0M solution of lithium aluminium hydride in THF for 30 minutes at room temperature and 1 h at reflux. Chromatography on flash silica, eluting with 30-40% ethyl acetate/petroleum ether, afforded 0.091 g (38%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent the title product hydrochloride was obtained as a white solid, m.p. 214°-223° C. (dec). NMR δ(D2O) 1.55 (1H, m), 1.68 (1H, m), 1.79-1.90 (2H, m), 2.62-2.75 (2H, m), 2.91-2.99 (3 H, m), 3.23 (1H, t, J=11.8 Hz), 3.54 (1H, m), 3.72 (1H, m), 4.44 (2H, s), 6.57 (1H, d of d, J=3.3 and 1.9 Hz), 6.75 (1H, d, J=3.2 Hz), 7.21-7.28 (3H, m), 7.33-7.36 (1H, m), 7.67 (1H, d, J=1.8 Hz). m/z (CI+, NH3) 268 (M+H)+, 200 (M-C4H3O)+, 124, 96, 81.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([N:8]2[CH2:14][C:13]3[C:15]([F:26])=[C:16]([Cl:25])[CH:17]=[C:18]([C:19]4([CH3:24])OCC[O:20]4)[C:12]=3[O:11][CH:10]([CH3:27])[C:9]2=[O:28])[CH2:5]1)(=[O:3])[CH3:2].Cl>CO.C(OCC)(=O)C.O>[C:19]([C:18]1[C:12]2[O:11][CH:10]([CH3:27])[C:9](=[O:28])[N:8]([CH:6]3[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:7]3)[CH2:14][C:13]=2[C:15]([F:26])=[C:16]([Cl:25])[CH:17]=1)(=[O:20])[CH3:24]
Reactant: CC(=O)N1CC(N2Cc3c(F)c(Cl)cc(C4(C)OCCO4)c3OC(C)C2=O)C1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(Cl)c(F)c2c1OC(C)C(=O)N(C1CN(C(C)=O)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
A solution of 4-(1-acetylazetidin-3-yl)-7-chloro-6-fluoro-2-methyl-9-(2-methyl-1,3-dioxolan-2-yl)-4,5-dihydro-1,4-benzoxazepin-3(2H)-one (190 mg, 0.460 mmol) in methanol (20 mL) and was treated with 6.0 M hydrogen chloride in water (1.15 mL, 6.90 mmol) and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired product (132 mg, 78%) as a mixture of enantiomers that was used without further purification. LCMS calculated for C17H19ClFN2O4(M+H)+: m/z=369.1; found: 369.1.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([CH3:31])[C:29]=1[OH:30])[C:23]([NH:25]O)=[NH:24])[CH3:19].Cl[CH2:33][C@@H:34]([OH:37])[CH2:35][OH:36]>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:10]3[O:12][N:25]=[C:23]([C:22]4[CH:27]=[C:28]([CH3:31])[C:29]([O:30][CH2:33][C@@H:34]([OH:37])[CH2:35][OH:36])=[C:20]([CH2:18][CH3:19])[CH:21]=4)[N:24]=3)[CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: OC[C@H](O)CCl
Reactant: COc1cc(C(=O)O)cc(C2CCCCC2)n1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCCC4)c3)n2)cc(C)c1OC[C@@H](O)CO

Procedure:
The title compound is prepared in analogy to Example 3 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid, 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine and (S)-3-chloro-1,2-propanediol; LC-MS: tR=1.16 min, [M+H]+=468.08; 1H NMR (CDCl3): δ1.33 (t, J=7.5 Hz, 3H), 1.34-1.40 (m, 1H), 1.40-1.52 (m, 2H), 1.57-1.69 (m, 2H), 1.77-1.84 (m, 1H), 1.87-1.95 (m, 2H), 1.99-2.08 (m, 2H), 2.41 (s, 3H), 2.70-2.81 (m, 3H), 3.83-4.00 (m, 4H), 4.03 (s, 3H), 4.15-4.21 (m, 1H), 7.32 (s, 1H), 7.49 (s, 1H), 7.88 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.[N:6]12[CH2:13][CH2:12][CH:9]([CH2:10][CH2:11]1)[C@H:8]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[CH3:24])[CH2:7]2.CN(C)C=O.Cl>CCCCCC.O1CCCC1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13]1)[C@H:8]([N:14]1[CH:1]=[CH:24][C:17]3[C:16](=[CH:21][CH:20]=[CH:19][C:18]=3[O:22][CH3:23])[C:15]1=[O:25])[CH2:7]2
Reactant: [Li]CCCC
Reactant: COc1cccc(C(=O)N[C@@H]2CN3CCC2CC3)c1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)n([C@@H]3CN4CCC3CC4)ccc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A solution of n-butyllithium (2.2 mmol) in hexane was added in a dropwise fashion to a stirred solution of (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-methylbenzamide (0.24 g, 0.87 mmol), from Example 1, Method B, in dry tetrahydrofuran (1.0 mL) at -70° C. The mixture was maintained at -10° C. and stirred for 1 hour. The mixture was then cooled to -70° C. and dimethylformamide (0.1 mL) added. The reaction mixture was allowed to warmto room temperature over 1.5 hours, then cooled to 0° C. and acidified with aqueous hydrochloric acid (10%). The layers were separated and the aqueous phase was washed with ethyl acetate. The aqueous layer wasthen made basic with aqueous sodium hydroxide (10N) and extracted with ethyl acetate (3×50 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. Evaporation of solvents gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-methoxy-1 (2H)-isoquinolinone as a white solid (0.23 g, 0.804 mmol). Preparation of the hydrochloride salt from ethanol-hydrogen chloride gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-methoxyl-1(2H)-isoquinolinone hydrochloride, m.p. 275°-277° C., [α]D25 -106.7° (c=0.30, H2O).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:10][C:8]([F:11])([F:9])[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:12])=[CH:7][N:6]=1
Reactant: Cc1ccc(C(F)(F)F)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(CBr)cn1

Procedure:
5-Methyl-2-trifluoromethylpyridine (see J. Org. Chem., vol. 29, pages 569-571) (8.1 g) was dissolved in 50 ml of carbon tetrachloride, and N-bromosuccinimide (8.9 g) and a catalytic amount of benzoyl peroxide were added. The mixture was refluxed for 7 hours with stirring. The reaction mixture was cooled, and insoluble materials were collected by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-trifluoromethyl-5-pyridylmethyl bromide (also known as 5-bromomethyl-2-trifluoromethylpyridine) (7.3 g).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[NH:8][C:9](=[O:11])[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14].O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1.CO[CH:29]([O:36][CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.O>[OH:1][C@@H:2]1[C@H:7]2[N:8]([CH:29]([O:36][CH3:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:9](=[O:11])[O:10][C@H:6]2[CH2:5][C@@H:4]2[CH2:12][O:13][CH:26]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:14][C@@H:3]12
Reactant: O=C1N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)C[C@@H]2O1
Reactant: COC(OC)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccccc1)N1C(=O)O[C@H]2C[C@@H]3COC(c4ccccc4)O[C@H]3[C@H](O)[C@H]21
Temperature: 60 °C
Yield: 735.8 %

Procedure:
To a solution of (3aR,4R,5R,6R,7aS)-4,5-dihydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (2.99 g, 14.7 mmol) in DMF (10 mL) at room temperature was added p-toluenesulfonic acid monohydrate (210 mg, 1.10 mmol) followed by benzaldehyde dimethylacetal (6.72 g, 44.2 mmol). The mixture was heated at 60° C. under slightly diminished pressure for 3.5 h. After cooling, the reaction was diluted with water (100 mL) and extracted with EtOAc (2×60 mL). The extracts were washed with brine and dried with MgSO4. The solvent was evaporated to give the crude product. This was purified by silica gel column, eluted with 10-30% EtOAc in hexanes to provide (3aR,4R,4aR,8aR,9aS)-4-hydroxy-3-(methoxy(phenyl)methyl)-6-phenyloctahydro-2H-[1,3]dioxino[5′,4′:4,5]benzo[1,2-d]oxazol-2-one (3.33 g, 55%). MS m/z 434.6 (M+23, 100%); 1H NMR (400 MHz, CDCl3) δ 7.30-7.51 (m, 10H), 6.20 (s, 1H), 5.52 (s, 1H), 4.47-4.50 (m, 1H), 4.24 (dd, J=11.1 Hz, 4.7 Hz, 1H), 4.17 (d, J=2.5 Hz, 1H), 3.83-3.88 (m, 1H), 3.69 (s, 3H), 3.55 (t, J=11.0 Hz, 1H), 3.40 (t, J=10.1 Hz, 1H), 3.26 (t, J=6.8 Hz, 1H), 2.11-2.23 (m, 2H), 1.28-1.36 (m, 1H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].CO.[CH3:13][O:14][C:15](=[O:29])[CH:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C@@H:21]([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15](=[O:29])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C@@H:21]([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: COC(=O)C1CCCN1[C@@H](C)c1ccccc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCN1[C@@H](C)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
L-tartaric acid (9.51 g) was mixed with methanol (14.18 g) and heated to 40° C. To the resulting solution was added dropwise a 50% toluene solution (28.93 g) of N-[(S)-α-methylbenzyl]-(RS)-proline methyl ester obtained in Example 1 at that temperature. After stirred at the temperature for 1 hour, the reaction mixture was cooled to 0° C. over 14 hours and stirred at that temperature for 2 hours. The crystallized solid was separated by filtration and washed with cold methanol to yield a salt of N-[(S)-α-methylbenzyl]-(S)-proline methyl ester and L-tartaric acid (11.50 g) in 98.8% diastereomeric excess (hereinafter referred to as “d.e.”) and a yield of 40.0%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:20]=1[C:19]([F:18])([F:32])[F:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 2,4-bis-trifluoromethyl-benzylbromide (126.6 mg, 0.40 mmol) and K2CO3 (83.01 mg, 0.60 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with EtOAc and filtered to give 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (96.0 mg, 52.4%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][CH2:17][C@@H:18]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:20]([C:29]3[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=3)[C:19]2=[O:36])=[CH:11][CH:10]=1.[CH2:38]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:39]#[CH:40]>CN(C=O)C.[Cu]I>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][CH2:17][C@H:18]2[C:19](=[O:36])[N:20]([C:29]3[CH:34]=[CH:33][C:32]([C:40]#[C:39][CH2:38][NH:41][S:42]([CH3:45])(=[O:44])=[O:43])=[CH:31][CH:30]=3)[C@@H:21]2[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(O)cc2)N1c1ccc(I)cc1
Reactant: C#CCNS(C)(=O)=O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCC#Cc1ccc(N2C(=O)[C@H](CC[C@H](O)c3ccc(F)cc3)[C@H]2c2ccc(O)cc2)cc1

Procedure:
Triethylamine (7 equivalents) is added to a solution of (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-1-(4-iodophenyl)azetidin-2-one (i-6) (1.00 equivalent), N-prop-2-yn-1-ylmethanesulfonamide (i-5) (1.50 equivalents), tetrakistriphenylphosphine palladium(0) (0.15 equivalents) and copper(I) iodide (0.30 equivalents) in DMF (0.1 M concentration with respect to final product) under a nitrogen atmosphere and the resulting solution aged at room temperature. After completion of reaction, the volatiles are evaporated in vacuo and the crude residue can be purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.O>O1CCCC1>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[C:18]([CH2:19][CH2:5][CH2:3][NH2:4])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NCCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.6 %

Procedure:
To an ice-bath cooled suspension of sodium hydride (1.32 g of a 60% dispersion in oil, 33 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere was added dropwise a solution of diethyl cyanomethylphosphonate (5.34 ml, 33 mmol) in tetrahydrofuran (40 ml) and the resulting mixture stirred at 0° C. for 15 minutes. To this mixture was added a solution of 3-trifluoromethylbenzaldehyde (5.22 g, 30 mmol) in anhydrous tetrahydrofuran (40 ml) and the resulting mixture stirred at room temperature for 1.5 hours. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×200 ml), brine (150 ml) then dried (Na2SO4) and evaporated. The residue was taken up in a mixture of ethanol (100 ml) and ammonium hydroxide (25 ml) and hydrogenated according to the method of Description 2. Purification by column chromatography on silica eluting with 5% MeOH in dichloromethane+0.5% NH4OH gave the title compound (1.5 g, 25%) as a yellow oil.
Reaction SMILES: C(N1CCC2C=CC(S([Cl:18])(=O)=O)=CC=2CC1)(=O)C.C(N1CCC2C=CC(SC)=CC=2CC1)(=O)C.C([N:38]1[CH2:44][CH2:43][C:42]2[CH:45]=[CH:46][C:47]([S:49]([CH3:51])=[O:50])=[CH:48][C:41]=2[CH2:40][CH2:39]1)(=O)C.Cl>>[ClH:18].[CH3:51][S:49]([C:47]1[CH:46]=[CH:45][C:42]2[CH2:43][CH2:44][NH:38][CH2:39][CH2:40][C:41]=2[CH:48]=1)=[O:50]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Reactant: CC(=O)N1CCc2ccc(S(C)=O)cc2CC1
Agent: CSc1ccc2c(c1)CCN(C(C)=O)CC2
Agent: Cl
Product: CS(=O)c1ccc2c(c1)CCNCC2

Procedure:
Following the procedure of Examples 4 and 5, 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine is converted to 3-acetyl-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine and then to 3-acetyl-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine which is hydrolyzed with dilute hydrochloric acid to give 7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [CH:1]1([CH:7]([O:40][CH3:41])[C:8]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:9]=2[CH2:10][N:11]([CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=2)[C:12]2[N:13]=[N:14][NH:15][N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].C(=O)([O-])[O-].[Na+].[Na+]>CC1OCCC1.CN(C=O)C>[CH:1]1([CH:7]([O:40][CH3:41])[C:8]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:9]=2[CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]([C:28]([F:29])([F:31])[F:30])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=2)[C:12]2[N:13]=[N:14][N:15]([CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nn[nH]n1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO[Si](C)(C)C(C)(C)C)n1)C1CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
To a mixture of N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2H-tetrazol-5-amine (40.4 mg, 0.068 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (25 mg, 22 μL, 0.10 mmol) in 2-MeTHF/DMF was added sodium carbonate (29.1 mg, 0.275 mmol). The slurry was stirred at 60° C. overnight. The reaction was diluted and filtered. The filtrate was concentrated and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in heptane) to afford the title compound (39.3 mg, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6H) 0.80 (s, 9H) 0.92-1.12 (m, 5H) 1.15-1.21 (m, 1H) 1.42-1.52 (m, 1H) 1.57-1.62 (m, 2H) 1.68-1.72 (m, J=2.90 Hz, 1H) 1.89 (d, J=12.44 Hz, 1H) 3.03 (s, 3H) 4.05-4.09 (m, 3H) 4.54 (t, J=5.60 Hz, 2H) 4.64-4.76 (m, 3H) 4.89 (d, J=16.17 Hz, 1H) 7.35 (s, 1H) 7.47 (d, J=7.88 Hz, 1H) 7.54 (d, J=9.12 Hz, 1H) 7.65 (s, 2H) 7.75 (s, 1H). MS (ES+) Calc: 753.3, Found: 754.6 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](I)=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([OH:20])[C:18]#[CH:19].O>CCN(CC)CC.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>[CH2:1]([O:8][C:9]1[C:10]([C:19]#[C:18][CH2:17][OH:20])=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Clc1ccc(OCc2ccccc2)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: OCC#Cc1nc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.3 %

Procedure:
A mixture of compound 3-(benzyloxy)-6-chloro-2-iodopyridine (2.5 g, 7.2 mmol), prop-2-yn-1-ol (443 mg, 7.9 mmol), Pd(PPh3)2Cl2 (280 mg, 0.4 mmol) and CuI (76 mg, 0.4 mmol) in Et3N (25 mL) was stirred at room temperature for 6 hours. Water (50 mL) was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (petroleum ether:ethyl acetate=2:1) to provide the product of compound 3-(3-(benzyloxy)-6-chloropyridin-2-yl)prop-2-yn-1-ol (1.8 g, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 7.42˜7.33 (m, 5H), 7.17 (s, 2H), 5.18 (s, 2H), 4.54 (s, 2H). MS (M+H)+: 274/276.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=3)=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCOCC1.[ClH:56]>O>[ClH:56].[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2ccccc2n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2ccccc2n1
Reaction time: 72 h

Procedure:
A mixture of 2-methyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) (890 mg) and a 7.5M solution of hydrogen chloride dioxane (10 ml) and water (1 ml) was allowed to stand for 72 hours. Volatile material was removed by evaporation and the residue was triturated with ether (2×50 ml). The ether was decanted off and the solid residue crystallised from isopropanol to give 2-methyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride (370 mg), as a white solid, m.p. 188°-190° C.; NMR (d6 -DMSO): 2.92(s,3H), 5.63(s,2H), 7.21(d,2H), 7.56-7.87(m,8H), 8.07(dt,1H), 8.28(dd,1H), 8.32(dd,1H); mass spectrum [-ve FAB, DMSO/NBA]: 392 (M-H)-, 158; microanalysis found: C,66.0; H,4.6; N,15.5%; C24H19N5O.HCl.0.5H2O requires: C,65.7; H,4.8; N,16.0%.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH:8]2[CH:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[CH:12]([C@:13]2([CH3:30])[CH:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)[CH3:3].C(Cl)(Cl)Cl.[CH3:38][OH:39]>>[CH3:3][CH:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([O:29][C:38]([CH2:6][C:7]([C:31]([OH:33])=[O:32])([CH3:24])[CH3:8])=[O:39])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)[CH3:1]
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CCC4[C@@]5(C)CC[C@H](O)C(C)(C)C5CC[C@]43C)C12
Reactant: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 24.5 %

Procedure:
yield 24.5% (starting with 155.9 mg of dihydrobetulinic acid); crystallization from MeOH—H2O gave colorless needles; mp 291°-292° C.; [α]D20-13.4° (c=1.1, CHCl3—MeOH [1:1], 1H NMR (pyridine-d5): 0.85, 0.94 (each 3H, d, J=7.0 Hz; 20-(CH3)2), 0.75, 0.93, 0.97, 1.01, 1.03 (each 3H, s; 4-(CH3)2, 8-CH3, 10-CH3, 14-CH3), 1.55 (6H, s; 3′-CH3×2), 2.89, 2.97 (each 1H, d, J=15.5 Hz; H-2′), 4.77 (1H, dd, J=5.0, 11.0 Hz, H-3); Anal. Calcd for C36H58O6.5/2H2O: C 68.43, H 10.04; found C 68.64, H 9.78.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(CCO)C.C(Br)(Br)(Br)[Br:21]>CCCCCC.C1COCC1>[Br:21][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccnc(Cl)c1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(Cl)nc(Br)c1

Procedure:
Starting with 2-chloro-4-methylpyridine II, treatment with n-butyllithium in the presence of N,N-dimethylaminoethanol in hexane, followed by addition of carbon tetrabromide in THF affords 2-bromo-6-chloro-4-methylpyridine III. Compound III undergoes a palladium coupling with boronic acid IV in the presence of a base, such as Na2CO3, in a suitable solvent, such as DME, to give chloropyridine V.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH2:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH2:30][CH3:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: CCN1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: CCN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(Cl)c4)c23)CC1
Yield: 70 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and N-ethylpiperazine to give the title compound in 70% yield; NMR Spectrum: 0.95 (t, 3H), 2.25 (q, 2H), 2.32 (br s, 4H), 2.45 (s, 3H), 2.50 (hidden by DMSO, 4H), 2.80 (t, 2H), 4.45 (t, 2H), 7.20 (d, 1H), 7.26 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 509 (MH+).