Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=[C:9]([Cl:11])[Cl:10])[CH:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[NH2:1][C:2]1[N:3]=[C:4]([Cl:15])[CH:5]=[C:6]([CH:8]=[C:9]([Cl:11])[Cl:10])[N:7]=1
Reactant: Nc1nc(O)cc(C=C(Cl)Cl)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)cc(C=C(Cl)Cl)n1

Procedure:
10 Parts of 2-amino-4-(2,2-dichlorovinyl)-6-hydroxypyrimidine and 66 parts of phosphorus oxychloride were heated together under reflux for 1 hour with stirring. The solution was cooled and excess phosphorus oxychloride was removed in vacuo on a rotary evaporator. The residual viscous oil was poured onto ice, with stirring. Solid sodium bicarbonate was added portionwise until the solution had pH 7-8. The precipitated solid was filtered, washed with water and dried. Recrystallisation from aqueous methanol gave 2-amino-4-chloro-6-(2,2-dichlorovinyl)pyrimidine m.p. 119°-120° C.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:48]([OH:49])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:50]([CH3:52])[CH3:51])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:50]([CH3:51])[CH3:52])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:48]([OH:49])[CH:41]1[O:40]3)[O:36]2)[CH2:45][CH2:46][CH3:47]
Reactant: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
20.5 mg of compound (37) was dissolved in 1 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×22 cm) and eluted with n-hexane-ethyl acetate (1:1) to give 8.8 mg of compound (38) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5]2.C([O-])(=O)C.[NH4+].[Br:25]N1C(=O)CCC1=O>CC#N>[NH2:1][C:2]1[C:3]([Br:25])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(N)ccc2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2c(Br)c(N)ccc2c1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
tert-Butyl (6-aminonaphthalen-2-yl)carbamate (1.31 g, 5.07 mmol) was stirred with ammonium acetate (39 mg, 0.5 mmol) in MeCN in an ice bath. N-Bromosuccinimide (948 mg, 5.32 mmol) was dissolved in additional MeCN and added slowly over 1 h. Stirring was continued for 1 h at 0° C., and then Celite was added. Solvents were removed under reduced pressure, and the product (1.33 g, 78%) isolated by silica gel chromatography eluting with a gradient of 0→50% EtOAc in heptanes. 1H NMR (CD2Cl2) d 7.94 (d, 1H); 7.89 (br d, 1H); 7.58 (d, 1H); 7.38 (dd, 1H); 7.02 (d, 1H); 6.66 (br s, 1H); 4.35 (br s, 2H); 1.54 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:32][CH3:33])(=O)=O.O>CN(C)C=O>[F:17][C@@H:16]1[C@@:11]2([C:10](=[O:21])[O:9][CH2:8][N:7]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:12]2[C@H:14]([C@@H:13]2[C:18]([O:20][CH2:32][CH3:33])=[O:19])[CH2:15]1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (1S,2S,3S,5R,6S)-3′-((allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid obtained below in Example A-1 (A-1-2, 200 mg) in N,N-dimethylformamide (6 mL), cesium carbonate (261 mg) was added, and the mixture was stirred at room temperature for 30 minutes. Ethyl tosylate (201 mg) was added and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed once with water and once with brine, sequentially, and then the ethyl acetate layer was dried over anhydrous sodium sulfate. The insoluble was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel cartridge, hexane:ethyl acetate=100:0-50:50) to give (1S,2S,3S,5R,6S)-3′-allyl 6-ethyl 3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-3′,6-dicarboxylate (Reference Example 1-1, 68 mg) as a colorless amorphous.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:30][C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[S:35][C:34]([C:36]([NH:29][CH:17]2[CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:20][N:15]([C:13]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:14])[CH2:16]2)=[O:37])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccc(Cl)s3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
65 mg (0.15 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 22 mg (0.13 mmol, 0.9 eq.) of 5-chlorothiophene-2-carboxylic acid were reacted according to General Method 1. Yield: 43 mg (72% of theory)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.COC1C=CC(C[C:22]2([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28](OCC)=[S:29])=CC=1.[C:42]([O:45]C(=O)C)(=[O:44])[CH3:43]>O1CCCC1>[C:42]([O:45][C:22]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:28]=2[S:29][C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=S)C1CCCCC1(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2sc3c(c2OC(C)=O)CCCC3)cc1
Reaction time: 0.25 h
Yield: 43.4 %

Procedure:
A solution of 1.5 mL (10.7 mmol) of diisopropylamine in 10 mL of dry tetrahydrofuran was cooled to -78° under nitrogen. To this was added 4 mL of 2.5M n-butyllithium (in hexane) and after 15 minutes, a solution of 1.36 g (3 mmol) of ethyl 2,2-bis-(4-methoxyphenyl)methylthiocyclohexanecarboxylate in 5 mL of dry tetrahydrofuran was added and the solution was stirred under N2 for 2 hours. Then 1.5 mL (15 mmol) of acetic anhydride was added and the solution was stirred at room temperature for 1 hour. The solution was partitioned between ether and NaHCO3 and the ether layer was washed with NaHCO3, then brine, and dried over MgSO4. The solution was concentrated and the residue chromatographed on silica gel (20% ethyl acetate-hexane) to afford a colorless oil. This was crystallized from ethyl acetate-hexane to afford 0.394 g (47%) of title compound as a white crystalline solid, m.p. 81° C. NMR (CDCl3, (CH3)4Si) δ1.81 (4H, m), 2.25 (3H, s, CH3CO), 2.35 (2H, t, J=6Hz), 2.71 (2H, t J=6Hz), 3.80 (3H, s, OCH3), 6.90 (2H, AB), 7.39 (2H, AB).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([NH:15][CH3:16])[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:20]O>>[CH3:20][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[C:13]([NH:15][CH3:16])=[CH:14][C:6]=1[Cl:5]
Reactant: CNc1cc(Cl)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CNc1cc(Cl)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Thionylchloride (3.87 g, 32 mmol) is added dropwise at rt to a mixture of 2-chloro-4-methylamino-5-nitro-benzoic acid (5.00 g, 22 mmol) and 45 mL MeOH and it is stirred at reflux overnight. The mixture is cooled to rt and the precipitate is collected by filtration and dried. Yield: 5.01 g. MS m/z: 245 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[C:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH:39]([CH3:45])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: CCOC(=O)C(C)=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)OCC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.0 g), rhodium(II) acetate (dimer) (0.027 g) and toluene (30 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl 2-diazopropionate (3.2 g) in toluene (30 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. A solution of ethyl 2-diazopropionate (1.6 g) in toluene (10 mL) was added, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.2 g, 88%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:20](OCC)(=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:20](=[O:29])[CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:22][CH:23]=1
Reactant: Cc1cccnc1
Reactant: CCOC(=O)c1ccc(OC)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cccnc2)cc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a stirred solution of diisopropylamine (33.2 mL) in dry tetrahydrofuran (300 mL) cooled at −78° C., was added a solution of 1.6 M n-butyllithium in hexane (148 mL) dropwise. After addition, the resulting mixture was stirred for 10 min at the same temperature, followed by the addition of β-picoline (20 g). The resulting mixture was allowed to warm up to −10-0° C. After an additional 20 min stirring, a solution of ethyl p-anisate (19.4 g) in dry tetrahydrofuran (40 mL) was added. After addition the mixture was stirred for another 1 h at ambient temperature, and water (100 mL) was added to the mixture. The solvent was removed under reduced pressure and the oily product was extracted with ethyl acetate. The extracts were washed with water, dried, and concentrated under reduced pressure. The crystalline residue was recrystallized from ethyl acetate—isopropyl ether to afford the title compound (20.8 g, yield 85%).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: OCc1ccccc1
Solvent: ClCCl
Product: O=C(CC(F)=C(F)F)OCc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 3,4,4-trifluoro-3-butenoyl chloride (2.8 g, 0.0176 mole) and benzyl alcohol (0.9 g, 0.0083 mole) in 20 mL dichloromethane is heated at reflux for 40 h. The solution is cooled to room temperature, diluted with dichloromethane (15 mL), washed successively with 5% sodium bicarbonate, water and brine, and dried. Evaporation of the solvent gave 1.75 g of analytically pure product as a pale yellow oil, a 92% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH:23]([N:26](C(C)C)CC)([CH3:25])[CH3:24].C(N)(C)C.C(OC(=O)C)C.Cl>C(#N)C.C(OCC)(=O)C.O>[ClH:1].[F:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:26][CH:23]([CH3:25])[CH3:24])[N:3]=[C:4]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:5]=2)=[CH:10][CH:11]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc(Nc3ccccc3)n2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)N
Product: CC(C)Nc1nc(Nc2ccccc2)nc(Nc2ccc(F)cc2)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A 316 mg portion of the 6-chloro-N-(4-fluorophenyl)-N′-phenyl-1,3,5-triazine-2,4-diamine was dissolved in 10.0 ml of acetonitrile, and 0.523 ml of diisopropylethylamine and 0.170 ml of isopropylamine were added thereto and stirred overnight at 80° C. The reaction solution was cooled down to room temperature, and then mixed with water and extracted with ethyl acetate. The organic layer was washed with 5% citric acid aqueous solution and saturated brine and then dried using anhydrous magnesium sulfate. The solvent was evaporated under a reduced pressure, and the thus obtained residue was applied to a silica gel column chromatography and eluted with ethyl acetate:n-hexane (2:1) to obtain a crude product. This crude product was dissolved in ethyl acetate and mixed with 4 M hydrochloric acid ethyl acetate solution, the solvent was evaporated under a reduced pressure, and the thus obtained residue was crystallized from ethyl acetate, thereby obtaining 327 mg of N-(4-fluorophenyl)-N′-isopropyl-N″-phenyl-1,3,5-triazine-2,4,6-triamine hydrochloride as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: Fc1ccc(CBr)cc1
Product: O=[N+]([O-])c1cc(OCc2ccc(F)cc2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-4-fluoro-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(4-fluoro-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.[CH:20](OCC)=[O:21]>>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][CH:20]=[O:21])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(CN)n1
Reactant: CCOC=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(CNC=O)n1

Procedure:
0.100 g (0.368 mmol) of 2-(1-methyl-3-trifluoromethyl-pyrazol-5-yloxy)-6-(aminomethyl)-pyridine in 5 ml of ethyl formate was heated at reflux for 3 h. The solution was then filtered through a cartridge packed with 3 g of silica gel and this cartridge was rinsed out with ethyl acetate. The filtrate was concentrated.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11](COCC[Si](C)(C)C)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])[C:8]2=[CH:7][N:6]=1.[H-].[Na+].C1(C)C=CC(S([O:46][CH2:47][CH:48]2[CH2:52]OC(C)(C)[O:49]2)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:52][CH:48]([OH:49])[CH2:47][OH:46])=[CH:16][C:15]=3[CH3:21])[C:8]2=[CH:7][N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reactant: Cc1cc(O)ccc1-c1nn(COCC[Si](C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(O)CO)ccc1-c1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 85 °C
Yield: 15.4 %

Procedure:
4-[6-(2,4-Difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenol (0.125 g, 0.26 mmol) from Example 12 was placed in a microwave tube together with dry DMF (3.0 mL) and sodium hydride (0.021 g of 60% suspension in mineral oil, 0.31 mmol). 2,2-Dimethyl-1,3-dioxolan-4-ylmethyl p-toluene sulfonate (0.91 g, 0.31 mmol) was added, and the tube was sealed and heated to 85° C. for five minutes via microwave. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic phase was separated, and the aqueous phase was washed twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was dissloved in 3 mL of 4 N HCl in dioxane, transferred to a sealed tube, and heated to 90° C. for 90 minutes. The reaction mixture was cooled, partitioned between water and ethyl acetate, and made basic by addition of aqueous sodium bicarbonate (to pH 9). The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC plate using methylene chloride/MeOH 93:7 to yield 0.016 g (0.04 mmol, 14.5%) of 3-{4-[6-(2,4-difluorophenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenoxy}-propane-1,2-diol. Mass Spec. M+H=429.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])[C:4]=3[CH:3]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Reactant: COc1cccc(B(O)O)c1
Agent: OB(O)c1ccccc1
Product: COc1cccc(-c2ccc3c(c2)C(c2cccc(C#N)c2)=NCC(=O)N3C)c1
Yield: 58 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 3-methoxyphenyl boronic acid. The title compound (110 mg) was obtained as a yellow solid, (yield=58%).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[OH:11])[CH2:4][CH2:3]1.[CH2:12]=[O:13].[Mg+2].[Cl-].[Cl-]>CC#N>[OH:11][C:6]1[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[O:13]
Reactant: CC1(c2ccccc2O)CC1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: CC1(c2cccc(C=O)c2O)CC1
Temperature: 25 °C
Yield: 56.7 %

Procedure:
step 1—To a solution of 2-(1-methylcyclopropyl)phenol (70, 0.55 g, 3.4 mmol; CASRN 433684-77-6) in MeCN (7 mL) was added paraformaldehyde (0.68 g, 23 mmol), MgCl2 (0.48 g, 0.051 mmol) and TEA (1.3 g, 13 mmol). The mixture was stirred and heated at reflux for 5 h. After cooling to RT, the reaction mixture was partitioned between DCM and 1M aqueous HCl, and the organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.34 g (58%) of 2-hydroxy-3-(1-methylcyclopropyl)-benzaldehyde (72) as a light yellow oil.
Reaction SMILES: [N:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:3]1([NH2:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=NN1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1CCCc2ccccc21
Temperature: 0 °C
Yield: 52.9 %

Procedure:
A solution of 1-nitroso-1,2,3,4-tetrahydroquinoline (10.0 g, 61.66 mmol) in 60 mL dry THF was added dropwise to a refluxing suspension of LiAlH4 (4.26 g, 112.21 mmol) in 130 mL THF. The reaction was allowed to reflux for 1 hour, cooled to 0° C., and then quenched by the dropwise addition of Rochelle's salt solution. The resulting precipitate was diluted with THF and filtered. The filtrate was then concentrated under reduced pressure, then purified by flash chromatography to give the product (4.83 g, 52.9%) as a white solid. 1H-NMR (300 MHz, CDCl3): δ 7.12 (m, 2H), 6.95 (d, 1H), 6.69 (m, 1H), 3.32 (m, 2H), 2.75 (t, 2H), 2.04 (dt, 2H) ppm; MS m/z calculated for C9H13NO (M+H): 149.1. Found 149.1 (M+H, ESI+).
Reaction SMILES: [C:1]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:17]2)[CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:17]2)[CH2:15][CH2:16]1
Reactant: O=C(CCN1CCC2(CC1)OC(c1ccccc1)c1ccccc12)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CCN1CCC2(CC1)OC(c1ccccc1)c1ccccc12)c1ccccc1

Procedure:
A solution of 2.5 g. of 1'-(2-benzoylethyl)-1,3-dihydro-3-phenylspiro[isobenzofuran-1,4'-piperidine], (Example 107), 30 ml. of methanol, and 0.35 g. of sodium borohydride is stirred at room temperature for 4 hours, diluted with water, and extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to provide 1,3-dihydro-1'-(3-hydroxy-3-phenylpropyl)-3-phenylspiro[isobenzofuran-1,4'-piperidine].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:11][C:10]([CH3:12])=[CH:9][C:8]=2[Cl:13])=[N:18][CH:19]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Cc1cc(Cl)c(OCCO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(Br)cn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A sol. of 2-(2,6-dichloro-4-methyl-phenoxy)-ethanol (18.6 g, 84 mmol) in THF (360 mL) was cooled to 0° C. NaH (about 55% in oil, 6.60 g, about 153 mmol) was added in portions, and the mixture was stirred at rt for 30 min. A sol. of 2,5-dibrompyridine (18.0 g, 76.3 mmol) in THF (60 mL) was added dropwise, and the mixture was heated to reflux for 90 min. The mixture was allowed to cool to rt, and ice was added carefully. The solvents were partially removed under reduced pressure, and the residue was diluted with EtOAc. This mixture was washed with aq. sat. NH4Cl. The aq. layer was extracted back with EtOAc (2×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 3:97) yielded the title compound (22.7 g, 79%). LC-MS: tR=1.13 min; ES+: 378.08.