Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:19])[C:10]=1[CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:19][C:9]1[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7][CH:8]=1
Reactant: [N-]=[N+]=NCc1cncc(Cl)c1COC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1cncc(Cl)c1COC1CCCCO1

Procedure:
A solution of 3-azidomethyl-5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (0.46 g, 1.6 mmol) and triphenylphosphine (0.43 g, 1.6 mmol) in THF (15 mL) and H2O (0.15 mL) was stirred at RT overnight. Solvents were concentrated in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaHCO3 solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 256.8 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:31]4[O:30][CH:34]=[CH:33][CH:32]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccco1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccco2)c1

Procedure:
Prepared as described in Example 83 using (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and furan-2-carboxylic acid (8 mg, 0.07 mmol). Yield 27 mg (78%).
Reaction SMILES: [Li][CH2:2]CCC.CC(C)=O.C(=O)=O.[CH:13]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=1.CI.Cl>C1COCC1>[CH3:2][C:17]1[C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=[CH:13][C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [Li]CCCC
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C=O)ccc2c1OCO2
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
n-BuLi (2.5 M in THF, 26.4 mL, 66 mmol) was added dropwise to a solution of N,N,N′-(trimethyl)ethylenediamine (8.6 mL, 6.79 g, 66.4 mmol) in THF (120 mL) at −78° C. (acetone-dry ice bath). After 15 min, piperonal (9.0 g, 60 mmol) was added, the mixture was stirred for 15 min, and n-BuLi (2.5 M in THF, 72 mL, 180 mmol) was added via syringe. After the reaction mixture was stirred for 1 h at −78° C., CH3I (22.4 mL, 50.92 g, 360 mmol) was added at −78° C. The mixture was stirred for 2 h at room temperature, poured into cold stirred 10% hydrochloric acid (prepared with 100 mL concentrated hydrochloric acid and 360 mL water), extracted with CHCl3 (400 mL×3), washed with brine (400 mL), dried (Na2SO4), filtered and concentrated to give the crude product. Purification by preparative flash chromatography (SiO2, EtOAc-hexane 10:1) gave the white crystalline product (6.71 g, 68.1%): mp 70-71° C. 1H NMR (300 MHz, CDCl3) δ 9.96 (s, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.04 (s, 2H), 2.50 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Cl-].[Ru+2].[Fe]>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11]
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: [Fe]
Agent: [Ru+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)O)cc1OC
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium(II) chloride (0.38 mg, 0.4 μmol, 0.1 mol %) and a chiral ligand (M=Fe, R=t-Bu, Ar=C6H5—, 0.26 μmol, 0.065 mol %) were dissolved in toluene (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 120° C. After the mixture was cooled to room temperature, 3,4-dimethoxyacetophenone (0.4 mmol), toluene (2 mL) and an aqueous solution of sodium carbonate (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (10 atm) at 25° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(3,4-dimethoxyphenyl)ethanol was obtained and the ee value (ee=96%) was measured by GC analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:14][CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:13]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25 mL rb flask was charged with 1.111 g (2.97 mmol) of the product of Step B, 1.451 g (4.45 mmol) Cs2CO3, 10 mL DMF and finally 0.5 mL (3.71 mmol) of bromopinacolone. The reaction mixture was stirred at room temperature 1 h then partitioned between EtOAc and water. The organic layer was washed with water, brine, then dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH2:12])=[N:7]2.I[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:2][C:3]1[N:4]=[C:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[N:7]2
Reactant: Cc1nc(-c2ccccc2)n2nc(N)ncc12
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccccc2)n2nc(Nc3ccc([N+](=O)[O-])cc3)ncc12
Temperature: 80 °C
Yield: 23.1 %

Procedure:
To a mixture of 5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine hydrochloride (0.026 g, 0.10 mmol), 1-iodo-4-nitrobenzene (0.027 g, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (2.7 mg, 0.0030 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5.6 mg, 0.0090 mmol) and sodium t-butoxide (0.025 g, 0.23 mmol) was added toluene (1 mL). The solution was heated to 80° C. for two hours. After cooling to room temperature, the solution was filtered, and silica gel (1 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (50:50) to ethyl acetate:hexanes (100:0) using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-N-(4-nitrophenyl)-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (0.0080 g) as a yellow solid. 1H NMR (CDCl3): δ8.86 (s, 1H), 8.78 (s, 1H), 8.48-8.40 (m, 2H), 8.26 (d, J=9.4 Hz, 2H), 7.81 (d, J=9.3 Hz, 2H), 7.61-7.36 (m, 3H), 2.65 (s, 3H). MS m/z 347 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[S:21][CH:22]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.[Li+].[OH-]>O>[S:21]1[CH:22]=[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]1=2
Reactant: CCOC(=O)C1(NC(=O)c2csc3ccccc23)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1csc2ccccc12
Reaction time: 18 h
Yield: 121.3 %

Procedure:
A 50 mL flask containing the 2-[(benzo[b]thiophene-3-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (182, 0.40 g, 1.10 mmol) is charged with 1,4-dioxane (10 mL) and MeOH 10 mL). A stirring bar is added and stirring is initiated. After dissolution, water (5.0 mL) is added followed by the LiOH (115 mg, 2.74 mmol). After 18 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Dilute aqueous HCl (3%, ˜15 mL) and EtOAc (25 mL) are added to the reaction flask. After stirring for 10 min, the contents of the flask are poured into a reparatory funnel. The layers are separated. The aqueous layer is extracted with EtOAc (30 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 450 mg of a dry white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.I[C:36]1[S:37][C:38]2[CH2:44][CH2:43][CH2:42][CH2:41][C:39]=2[N:40]=1.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC.O.C(Cl)Cl.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([C:36]4[S:37][C:38]5[CH2:44][CH2:43][CH2:42][CH2:41][C:39]=5[N:40]=4)[C:22]([NH2:34])=[N:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1
Reactant: Ic1nc2c(s1)CCCC2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(s1)CCCC2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (30 mg, 0.064 mmol), 2-iodo-4,5,6,7-tetrahydrobenzothiazole (20 mg, 0.077 mmol), potassium carbonate (26 mg, 0.19 mmol), and Pd(PPh3)4 (7.4 mg, 0.0064 mmol) in DME (1.5 mL) and H2O (0.5 mL) was evacuated and refilled with N2 (3×). It was then heated at 100° C. for 30 min in the microwave reactor. The mixture was diluted with EtOAc (30 mL), washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Hex.:EtOAc=30:70→15:85) to give a yellow solid. This material was dissolved in DCM (2 mL) and treated with IM HCl in diethyl ether (3 mL). The resulting mixture was stirred at room temperature for 3 h. The title compound was collected by filtration as a yellow solid, washed with DCM, and dried in vacuo. 1H NMR (DMSO-d6, 400 MHz): δ=1.82-1.88 (m, 4H), 2.14-2.23 (m, 4H), 2.81-2.87 (m, 4H), 3.35-3.40 (m, 2H), 4.55 (mc, 1H), 8.09 (s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.47 (s, 1H), 8.50 (d, J=2.0 Hz, 1H). MS (ES+): m/z=381.17 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][C:4]=1[Cl:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:15])[CH3:1])=[C:4]([Cl:14])[CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CN(C)c1ccc(C2CCCN2)cc1Cl
Product: CN(C)c1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1Cl

Procedure:
The title compound, white solid, m.p. 103° C. and MS: m/e=398 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-dimethylamino-3-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[N:15]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:14]=1)=[O:12])[CH3:9].Cl.Cl.[CH3:32][O:33][C@H:34]1[C@H:38]([NH:39][CH3:40])[CH2:37][NH:36][CH2:35]1>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[N:17][C:18]([N:36]3[CH2:37][C@@H:38]([NH:39][CH3:40])[C@H:34]([O:33][CH3:32])[CH2:35]3)=[CH:19][CH:20]=2)[N:15]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Reactant: CN[C@@H]1CNC[C@H]1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NC)[C@H](OC)C3)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
Triethylamine (18 ml) was added to a suspension composed of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (7.1 g) obtained in Example A-1 (4), trans-3-methoxy-4-methylaminopyrrolidine dihydrochloride (6.0 g) and acetonitrile (150 ml). The resulting reaction mixture was stirred at room temperature for 5 hours, and was then concentrated under reduced pressure. Then, an aqueous solution of sodium hydrogencarbonate was added, and the resultant mixture was extracted with chloroform. After the obtained extract was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent chloroform:methanol=6:1), and thus, there was obtained 1,4-dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (6.1 g).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Cl>CS(C)=O.C(OCC)(=O)C>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][CH:13]=2)=[N:1][N:2]=[N:3]1
Reactant: OCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 12 °C
Reaction time: 1 h

Procedure:
A mixture of [2′-(1H-tetrazol-5-yl)-biphenyl-4-yl]-methanol (1.03 g; 4.0 mmol), triethylamine (2.80 mL; 20 mmol) and dimethylsulfoxide (2 mL) is cooled to 12° C., and a solution of sulfur trioxide pyridine complex (1.27 g; 8.0 mmol) in dimethylsulfoxide (6.4 mL) is added over 10 minutes. The resulting clear solution is stirred at room temperature for almost 48 hours during which time more triethylamine (0.28 mL; 2.0 mmol) is added. The mixture is diluted with ethyl acetate (10 mL), cooled to 0 to 5° C. and slowly treated with a 2 M aqueous hydrochloric acid solution (15 mL). The aqueous layer is separated and extracted with ethyl acetate (10 mL). The combined organic layers are diluted with ethyl acetate (10 mL), washed with a 2 M aqueous hydrochloric acid solution (15 mL), twice with a 1 M aqueous hydrochloric acid solution (10 mL) and with a 10% aqueous solution of sodium chloride (10 mL). The organic extract is concentrated at 45° C. under reduced pressure to a volume of about 4 to 5 mL. The resulting suspension is stirred at room temperature for 45 minutes and at 0 to 5° C. for one hour before it is filtered. The solids are washed with cold ethyl acetate (2 mL) and dried at 45° C. under reduced pressure to give 2′-(1H-tetrazol-5-yl)-biphenyl-4-carbaldehyde as white, crystalline solid. A second crop can be obtained by concentrating the mother liquor to a volume of about 1 mL and filtering the solid formed.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:9]=1)=O)C>CCO>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:10]2[N:9]=[C:8]([CH2:6][OH:5])[C:13]([O:14][CH2:15][CH3:16])=[C:12]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:11]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1c(CO)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Yield: 79.6 %

Procedure:
NaBH4 (192 mg, 5 eq.) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (378 mg, 1 eq.) in EtOH (12 ml) and the mixture reacted to reflux overnight. The mixture was quenched with H2O, the solvent removed in vacuo, and the residue extracted with EA and washed with brine. The crude was purified by chromatography to give a product (267 mg, 80%).
Reaction SMILES: [C:1](O)(=O)C(O)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C.ClC(OCC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)(Cl)Cl.O1CCCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[O:11][CH:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][N:14]([CH3:1])[CH2:13]1
Reactant: O=C(O)C(=O)O
Reactant: Clc1cccc(OC2CNCCc3ccccc32)c1
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCc2ccccc2C(Oc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled solution of 1-(m-chlorophenoxy)-2,3,4,5-tetrahydro-3-benzazepine of Example 4, (6.5 g., 0.024 mole) and triethylamine (2.8 g, 0.028 mole) in chloroform (75 ml) was slowly dropped ethyl chloroformate (3.0 g, 0.028 mole) in chloroform (10 ml.). The reaction mixture was stirred overnight, about 16 hours, at ambient temperature, then was concentrated to an oil which was dissolved in ether, washed with water, dilute HCl, again twice washed with water, then dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil (7.5 g, 90%). A solution of the oil in tetrahydrofuran (THF) (75 ml) was slowly dropped into a refluxing suspension of LiAlH4 (1.6 g. 0.042 mole) in THF (125 ml). After refluxing five hours, the mixture was cooled, then was quenched by dropwise addition of saturated NH4Cl solution. The mixture was diluted with ether, filtered, washed twice with water then dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, then concentrated to an oil (5.6 g., 93%). This oil was distilled to yield an oil of 1-(m-chlorophenoxy)-3-methyl-2,3,4,5-tetrahydro-3-benzazepine (150°-170° C./0.1 mm).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-:16])=[O:15])[C:5]1=[O:17].C(N(CC)C(C)C)(C)C.[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl.CN(C)C=O>[C:27]([O:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-:16])=[O:15])[C:5]1=[O:17])(=[O:29])[CH3:28]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1CCO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OCCn1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
2-(2-Hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (2.2 g, 0.0089 mol) was dissolved in the mixture of methylene chloride (20 mL) and N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (2.33 mL, 0.0134 mol) and acetyl chloride (1.06 g, 0.0134 mol) were added and the reaction mixture was stirred at room temperature for 30 min. The volatiles were removed, and the residue was washed by water and then with diethyl ether to obtain the product as light yellow solid (2.45 g). MS m/z=277.0 (M+1).
Reaction SMILES: Cl.C(O[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[NH2:6])C.[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([NH:35][NH2:36])=O)[CH2:28][CH2:27]1)(=[O:25])[CH3:24].C[O-].[Na+]>CO>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[NH:6][C:5]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:36][N:35]=2)[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCN(CC(=O)NN)CC1
Reactant: CCOC(N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCN(Cc2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)CC1
Yield: 5.2 %

Procedure:
The procedure described for Example 283 B was followed using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methaneamine hydrochloride (600 mg, 1.88 mmol), 2-(4-acetylpiperazinyl)-N-aminoacetamide (1.12 g, 5.64 mmol), sodium methoxide (1.3 mL, 5.64 mmol), and methanol (8 mL) to yield the title compound (41 mg, 5% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.6 (s, 1H), 8.0 (m, 5H), 7.6 (m, 2H), 7.4 (t, 3H), 4.6 (m, 2H), ES-MS (m/z) 420 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=O)=O)=[CH:4][CH:3]=1.ClC1C=CC(S)=CC=1.C(=O)([O-])[O-].[K+].[K+].BrC(F)(F)F>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:11]([F:14])([F:12])[F:13])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Agent: FC(F)(F)Br
Agent: O=C([O-])[O-]
Agent: Sc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: FC(F)(F)Sc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
This example illustrates the preparation of several types of perfluoroalkylsulfonylphenyl ethers. Each of these illustrated ethers are produced in (a)-(e), below. Unless otherwise indicated, the reactions described below are performed in a 250 mL, 3-necked flask equipped with a mechanical stirrer, a reflux condenser topped with a nitrogen inlet tube, and a stopper. These illustrations utilize a starting material of 1-chloro-4-(trifluoromethylsulfonyl)benzene which may be prepared as described below. First, 1-chloro-4-trifluoromethylthiobenzene is prepared as follows: ##STR11## A mixture was formed in the flask from the following materials: 73 grams (g) of 4-chlorothiophenol, 400 milliliters (mL) of dimethyl formamide (DMF), and 70 g of potassium carbonate (K2CO3). This mixture was stirred at 60° C. for one hour and cooled to ice water bath temperatures (between about 0° C. and about 5° C.) and 100 g of bromotrifluoromethane (BrCF3) was bubbled into the mixture for two hours. The mixture was then stirred for two hours while warming to room temperature (about 23° C.) and then poured into 300 mL of water with stirring to form a product. The product was extracted with 300 mL of methylene chloride, separated, and washed with 250 mL of water. The product-containing, methylene chloride phase was separated and then dried by passing it through sodium sulfate. Low boiling point (up to 100° C., unless stated otherwise) components of the product phase ("low boilers") were then distilled off under reduced pressure (about 0.5 mm Hg) and the remaining product was then distilled over a short distillation column under reduced pressure to produce an 80% yield of an oily product. The identity of the product was confirmed by gas chromatography-mass spectroscopy (GC-MS) spectra to be 1-chloro-4-trifluoromethylthiobenzene.