Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][NH:19][CH2:18][CH2:17][NH:16]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:29]1[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[N:30]=1>>[CH:1]1([N:7]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:16][CH2:17][CH2:18][N:19]([C:29]4[N:34]([CH3:35])[C:33](=[O:36])[CH:32]=[C:31]([C:37]5[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=5)[N:30]=4)[CH2:20]3)=[CH:11][CH:10]=2)[CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1ccc([C@H]2CNCCN2)cc1)C1CCCCC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCN2)cc1)C1CCCCC1
Reaction time: 4.5 h
Yield: 85.9 %

Procedure:
To a solution of (S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl) piperazine (50 mg, 0.183 mmol) and triethylamine (0.077 mL, 0.55 mmol) was added 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (37 mg, 0.17 mmol) at room temperature. After stirring for 4.5 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by a reverse phase chromatography eluting 0.05% TFA in water-acetonitrile to afford (S)-2-(3-(4-(N-cyclohexyl-N-methylamino)phenyl)piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (67 mg, 88%) as a oil, which was dissolved in ethyl acetate and treated with 4 N hydrogen chloride in ethyl acetate to yield its trihydrochloride.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[CH:21][CH:20]=2)[C:8]=1[C:9]([O:11]C)=[O:10])(=O)C.[OH-].[K+]>CCO>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:7]([CH2:6][CH2:5][SH:4])[C:8]=2[C:9]([OH:11])=[O:10])=[CH:24][CH:23]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1ccc(COc2cccc(CCSC(C)=O)c2C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(COc2cccc(CCS)c2C(=O)O)cc1
Yield: 46.3 %

Procedure:
To a deoxygenated solution of 2-[2-(acetylthio)ethyl]-6-[4-(methoxycarbonyl)phenyl]methoxy-benzoic acid, methyl ester (0.20 g, 0.50 mmol) in 95% EtOH (3 mL) was added a deoxygenated solution of KOH (0.463 g, 8.3 mmol) in 95% EtOH (3 mL) under nitrogen. The solution was heated at reflux overnight and quenched by addition of 1 N HCl (20 mL). The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with water and brine, then dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1:1 dichloromathane/hexanes with 1% acetic acid) provided 2-[(4-Carboxyphenyl)methoxy]-6-(2-mercaptoethyl)-benzoic acid (0.077 g, 46%) as a white solid: 1H NMR (CD3OD) δ 2.75 (m, 2H), 2.92 (m, 2H), 5.22 (s, 2H), 6.93 (d, J=7.5 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 7.30 (t, J=8.3 Hz, 1H), 7.55 (d, J=7.9 Hz, 2H), 8.02 (d, J=8.0 Hz, 2H); 13C NMR (CD3OD) δ 26.5, 39.8, 71.1, 112.4, 123.9, 126.9, 128.3, 131.3, 131.7, 131.8, 139.9, 144.2, 156.7, 170.0, 172.3. Anal. Calcd for C17H16O5S: C, 61.43; H, 4.85; S, 9.65. Found: C, 61.16; H, 4.95; S, 9.44.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18](O)=[O:19])=[CH:8]1.O.OS(O)(=O)=O>C1COCC1.CCOCC>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:8]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCCc1c[nH]c2ccccc12
Temperature: 10 °C

Procedure:
LiAlH4 (1.21 mg, 31.71 mmol) was initially introduced into dry THF (50 ml). A solution of 3-indolepropionic acid (2.5 g, 13.21 mmol) in dry THF (80 ml) was added dropwise to the suspension in the course of 30 min. Thereafter, the reaction mixture was heated under reflux for 3 h at 10° C. and then stirred at RT for 18. H2O (60 ml) was subsequently added, and then a mixture of conc. H2SO4 (10 ml) and H2O (30 ml). The mixture was stirred for 20 min and ether (50 ml) was finally added. The organic phase was separated off and the aqueous phase was extracted with ether (3×40 ml). The combined ethereal extracts were dried over Na2SO4 and, after filtration of the drying agent, concentrated to dryness on a rotary evaporator. 3-(1H-Indol-3-yl)propanol was obtained as a viscous oil (2.28 g, 99%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH:25]=O)[CH:2]=[CH2:3].C(OC(=O)[NH:34][C@H:35]([C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH2:36][SH:37])(C)(C)C.C([SiH](CC)CC)C>ClCCl>[CH2:1]([O:4][C:5](=[O:27])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:23])([CH3:24])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:37][CH2:36][C@H:35]([NH2:34])[C:38]1[O:42][N:41]=[C:40]([CH3:43])[N:39]=1)[CH:2]=[CH2:3]
Reactant: Cc1noc([C@H](CS)NC(=O)OC(C)(C)C)n1
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Reaction time: 18 h
Yield: 74.9 %

Procedure:
To a solution of 13.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-benzoic acid allyl ester in 38 ml of trifiuoroacetie acid, cooled to 0° C., were added within 15 min a solution of 13.7 g of (R)-2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylcarbamic acid tert-butyl ester and 6.2 g of triethylsilane in 38 ml of dichloromethane. The solution was kept at 0° C. for 18 h and then evaporated in vacuo. The residue was taken up in ethyl acetate and the solution was successively washed with water, saturated sodium carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield 14.1 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanyl-methyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester as a pale yellow oil.
Reaction SMILES: BrCC[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([OH:13])(=[O:12])=[O:11].[Br:14][CH2:15][CH2:16]C1C=C(S(O)(=O)=O)C=CC=1>>[Br:14][CH2:15][CH2:16][C:8]1[CH:9]=[CH:4][C:5]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)c1ccccc1CCBr
Reactant: O=S(=O)(O)c1cccc(CCBr)c1
Product: O=S(=O)(O)c1ccc(CCBr)cc1

Procedure:
As a result, a mixture of 2-(2-bromoethyl)benzenesulfonic acid, 3-(2-bromoethyl)benzenesulfonic acid, and 4-(2-bromoethyl)benzenesulfonic acid was obtained, and the mixture was separated and purified with a silica gel column.
Reaction SMILES: [Si:1]([O:5][Si]([O-])([O-])[O-])([O-:4])([O-:3])[O-:2].[Na+:10].[Na+].[Na+].[Na+].[Na+].[Na+]>O>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:10].[Na+:10].[Na+:10].[Na+:10]
Reactant: [O-][Si]([O-])([O-])O[Si]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
Amorphous sodium disilicates with a low water content of 0.3 to 6% by weight are known from European patent application EP-A-0 444 415. The amorphous sodium disilicate is said preferably to contain 0.5 to 2% by weight of water. These amorphous disilicates with their very low water contents are produced by a multistage process in which a powder-form amorphous sodium silicate with a water content of 15 to 23% by weight is initially prepared. This material is treated in countercurrent with waste gas at temperatures of 250° to 500° C. in a revolving tube furnace. The amorphous sodium silicate leaving the revolving tube furnace is size-reduced to particle sizes of 0.1 to 12 mm by means of a mechanical crusher and is then ground in a mill to particle sizes of 2 to 400 pm.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:10]#[C:11][CH2:12][CH2:13][CH3:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].O.CC(C)=O>[CH2:12]([C:11]1[N:3]=[N:2][N:1]([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH:10]=1)[CH2:13][CH3:14]
Reactant: C#CCCC
Reactant: [N-]=[N+]=Nc1ccncc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1cn(-c2ccncc2)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-azidopyridine (4.65 g, 38.7 mmol) and pent-1-yne (4.12 ml, 41.8 mmol) were added into a 250 mL round-bottom flask with 50 mL mixture of water/acetone. Copper(II) sulfate (0.060 g, 0.376 mmol) and sodium L-ascorbate (0.256 g, 1.292 mmol) were added to this solution and the reaction was stirred at room temperature for 24 hours. Additional sodium ascorbate (0.103 g) was added. The solution was filtered and concentrated. Ethyl acetate (200 ml) was added to the concentrated solution. The organic layer was washed twice with 25 mL water, dried with MgSO4, filtered, concentrated and dried in vacuo, producing 4-(4-propyl-1H-1,2,3-triazol-1-yl)pyridine.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15](=[O:27])[N:14]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:13]=[CH:12]3)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>ClCCl>[CH2:20]([S:19][C:18]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][N:14]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:15]2=[O:27])=[CH:10][C:9]=1[O:8][C@@H:5]1[CH2:4][CH2:3][C@H:2]([NH:1][C:44](=[O:46])[CH3:45])[CH2:7][CH2:6]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](N)CC4)c(SCc4ccccc4)cc3c2=O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(SCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
45 mg (0.073 mmol) of 6-(4-amino-cis-cyclohexyloxy)-7-benzylsulfanyl-2-(4-methoxy-benzyl)-2H-iso-quinolin-1-one (127) were dissolved in 5 ml of dichloromethane and 14.8 mg (0.146 mmol) of triethylamine were added. At 0° C., 6.9 mg (0.088 mmol) of acetylchloride were added and the solution was stirred at room temperature. After 2 h, dichloromethane was added and the solution was washed with 2 N HCl and saturated sodium bicarbonate solution. After drying with magnesium sulfate and evaporation of the solvent, the title compound was isolated as crude product, which was used without further purification. Rt=1.53 min (Method C). Detected mass: 543.6 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:13](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)[C@@H](CO)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
25.5 g of the crude N-benzyloxycarbonyl-3(S)-amino-2(R)-p-toluenesulfonyl-4-phenyl-1-butanol obtained in the above Example 1 was dissolved in 750 ml of methanol. Then 13.9 g of potassium carbonate was added thereto at 10° C. and the resulting mixture was stirred for 3 hours at 10° to 20° C. The pH value of the reaction mixture was adjusted to 7 to 7.5 by adding a 5% aqueous solution of citric acid. After distilling off the solvent under reduced pressure, 150 ml of water was added to the concentrate. Then it was extracted with 150 ml portions of ethyl acetate twice and the extract was washed with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate and distilling off the solvent under reduced pressure, 14.4 g of crude N-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:30]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:30]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCNCC5)c4)C3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(N5CCNCC5)c4)C3)CC2)cc1
Temperature: 60 °C
Yield: 77.5 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-(3-(piperazin-1-yl)phenoxy)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D156) (105 mg, 0.186 mmol) in a mixture 1-4-dioxane/water (3 ml/1 ml), 1N NaOH (0.28 ml) was added. The reaction mixture was heated to 60° C. overnight. After cooling at room temperature, the reaction mixture was acidified with 1N HCl (pH=1) and the solvents were evaporated in vacuo. The residue was loaded on Porapak RXN RP cartridge (5 g) eluting with water+0.1% acetic acid/acetonitrile+0.1% acetic acid from 90/10 to 0/100. Collected fractions after solvente evaporation afforded the title compound (E21) (79 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BrH:18]>C(OCC)(=O)C.C(O)(=O)C.[Cu](Br)Br>[Br:18][CH:9]([S:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:17]
Reactant: Br
Reactant: O=C(CSc1ccccc1)c1ccccc1F
Agent: Br[Cu]Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(c1ccccc1F)C(Br)Sc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 1-(2-fluorophenyl)-2-(phenylthio)ethanone (413 mg) in ethyl acetate (6 mL) were added copper (II) bromide (419 mg) and a 47% solution (2 drops) of hydrogen bromide in acetic acid and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield 503 mg, yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]3([C:27]4[CH:28]=[N:29][N:30](C5CCCCO5)[CH:31]=4)[CH2:24][O:23]C(C)(C)[O:21][CH2:20]3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[ClH:43].O1CCOCC1>CO.O>[ClH:43].[F:42][C:38]1[CH:39]=[CH:40][CH:41]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:18][C:19]([C:27]3[CH:31]=[N:30][NH:29][CH:28]=3)([CH2:20][OH:21])[CH2:24][OH:23])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(c2cnn(C3CCCCO3)c2)COC(C)(C)OC1
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)(CO)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 75 mg of 8-[(2,6-difluorobenzyl)oxy]-N-{2,2-dimethyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1,3-dioxan-5-yl}-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 0.4 ml of methanol and 0.4 ml of water was added 1.6 ml of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain 74 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[1,3-dihydroxy-2-(1H-pyrazol-4-yl)propan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:20]1[C:25]([C:26]2[N:31]=[C:30]([CH3:32])[N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:24][C:23]([O:34][CH3:35])=[CH:22][N:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[NH2:33][C:28]1[N:29]=[C:30]([CH3:32])[N:31]=[C:26]([C:25]2[C:20]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:21][CH:22]=[C:23]([O:34][CH3:35])[CH:24]=2)[N:27]=1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)N2CCOCC2)c1
Reactant: COc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(Nc2cnc(Cl)c(NS(=O)(=O)N3CCOCC3)c2)c(-c2nc(C)nc(N)n2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 11.2 %

Procedure:
To a stirred solution of N-(5-amino-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.0819 g, 0.280 mmol) and 4-(2-fluoro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (Example 330 step 5, 0.0621 g, 0.264 mmol) in DMF (1 mL) in 5 mL microwave vial, NaHMDS (Aldrich, 1 M in THF, 1.06 mL, 1.06 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 45 min. The reaction mixture was partitioned between saturated aqueous ammonium chloride (30 mL) and 25% isopropanol in chloroform (20 mL). The aqueous phase was acidified to pH 3 to 4 then extracted with 25% isopropanol in chloroform (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The fraction was collected and the solvent was evaporated to give a red solid. The solid was partitioned between tris-HCl buffer (1 M, pH 7.0) and 25% IPA in CHCl3. The aqueous phase was acidified to pH about 3 then extracted with 25% IPA in CHCl3. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. This material was dissolved in about 1 mL DMSO and about 2 mL of water was added. The resulting solid was collected via filtration and washed with copious amount of water and dried to afford N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-methoxypyridin-2-ylamino)-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.015 g, 11% yield) as a dark yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br. s., 1H) 9.73 (br. s., 1H) 8.79 (br. s., 1H) 8.52 (br. s., 1H) 8.38-8.47 (m, 1H) 8.18 (br. s., 1H) 7.76-7.99 (m, 2H) 3.86 (br. s., 3H) 3.57-3.66 (m, 4H) 3.09-3.21 (m, 4H) 2.45 (br. s., 3H). m/z (ESI, positive ion): 508.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(CCc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methyl-2-thienyl)-2-naphthalenyl]ethynylbenzoate (Compound 33) (35.0 mg, 0.082 mmol) in 2 ml of EtOH and 1 ml THF at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was stirred at room temperature overnight and then acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.03 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.54-7.48 (3H, m), 6.89 (1H, m), 6.18 (1H, t, J=4.7 Hz), 2.49 (3H, s), 2.35 (2H, d, J=4.7 Hz), 1.32 (6H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:31]2[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])[C:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[Si]([N:52]=[N+:53]=[N-:54])(C)(C)C>ClCCl>[CH2:16]([O:15][C:14]1[CH:13]=[C:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:31]2[CH:36]=[C:35]([CH:37]([CH3:39])[CH3:38])[CH:34]=[CH:33][C:32]=2[O:40][CH3:41])=[CH:10][C:9]=1[C:7]1[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:54]=[N:53][N:52]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COCCCNC(=O)c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COCCCn1nnnc1-c1cc(-c2cc(C(C)C)ccc2OC)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
4,6-Bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid-(3-methoxypropyl)-amide (183 mg, 0.33 mmole) was dissolved in anhydrous dichloromethane (5 ml), then PCl5 (0.5 mmol) was added and the resulting solution was stirred at r.t. for 3 hr. TMSN3 (0.3 ml, neat, excess) was added and the resulting mixture was stirred at r.t. for 3 hr. After quenching the reaction with NaHCO3 solution, and extracting with dichloromethane (20 ml×3), the combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give product 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (166 mg, 87%). M.p.: 102-104° C.; 400 MHz 1H NMR (CDCl3) δ: 7.43 (s, 1H), 7.35-7.13 (m, 12H), 6.87 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 5.07 (s, 2H), 5.03 (s, 2H), 4.34 (t, J=7.2 Hz, 2H), 3.72 (s, 3H), 3.24 (t, J=6.0 Hz, 2H), 3.16 (s, 3H), 2.93-2.81 (m, 1H), 2.06 (pent, J=6.4 Hz, 2H), 1.23 (d, J=6.9 Hz, 6H); LCMS: 579 [M+H].
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]#[C:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:13]=[CH:12][C:11]=1[O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[O:26][C:11]1[CH:12]=[CH:13][C:14]([C:16]#[C:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][C:10]=1[CH2:9][NH:7][CH3:6]
Reactant: CN(Cc1cc(C#CCCN2CCOCC2)ccc1Oc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(C#CCCN2CCOCC2)ccc1Oc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a solution of [2-(3,4-dichloro-phenoxy)-5-(4-morpholin-4-yl-but-1-ynyl)-benzyl]-methyl-carbamic acid tert-butyl ester (95.6 mg, 0.18 mmol) in DCM (2 mL) was added TFA (1 mL). After 30 min, the mixture was concentrated and the residue was purified by FCC to give the desired product (67.7 mg, 89%). MS (ESI): mass calcd. for C22H24Cl2N2O2, 418.12; m/z found, 419.3 [M+H]+. 1H NMR (CDCl3): 7.49-7.47 (m, 1H), 7.37 (d, J=8.8, 1H), 7.27 (dd, J=8.3, 2.0, 1H), 7.02 (d, J=2.8, 1H), 6.82-6.78 (m, 2H), 3.75-3.69 (m, 6H), 2.70-2.64 (m, 2H), 2.62-2.57 (m, 2H), 2.55-2.51 (m, 4H), 2.42 (s, 3H), 1.80-1.69 (m, 1H).