Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH3:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:9]O>>[O:1]=[C:2]([CH2:7][CH3:8])[CH2:3][C:4]([O:6][CH3:9])=[O:5]
Reactant: CO
Reactant: CCC(=O)CC(=O)O
Product: CCC(=O)CC(=O)OC

Procedure:
The β-keto acid (14) is then esterified with an alkanol of formula R3 -OH to yield a β-keto ester (15). For example, 3-oxopentanoic acid is heated at reflux with methanol to yield methyl 3-oxopentanoate (15) (Scheme V, Step 3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:15](Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)[CH3:16]
Reactant: CCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Methyl 3-hydroxyphenylacetate (132.5 g, 0.80 mole) was added dropwise to a suspension of 50% NaH (43.2 g, 0.90 mole) in DMF (ie) at 0° C. under N2. The solution was stirred 1 hour at room temperature, cooled in an ice bath, and ethyl bromide (120 ml, 1.6 mole) added. The reaction mixture was stirred overnight at room temperature, filtered, and concentrated in vacuo. A solution of the residue in diethyl ether was washed with dilute NaOH solution and saturated NaCl, dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate: hexane (1:39→1:9) to give methyl 3-ethoxyphenylacetate (94.9 g). 1H NMR (DMSO-d6, 200 MHz) δ: 1.30 (t, J=7 Hz, 3H, ethyl CH3), 3.59 (s, 3H, ester CH3), 3.61 (s, 2H, ARCH2), 3.98 (q, J=7 Hz, 2H, ethyl CH2), 6.78-6.81 (m, 3H), 7.16-7.24 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:25][CH:24]2[NH:26][C:27]2[S:28][CH2:29][C:30](=[O:32])[N:31]=2)=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:29]3/[C:30](=[O:32])[N:31]=[C:27]([NH:26][CH:24]4[CH2:25][CH:23]4[C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[S:28]/3)[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccnc2ccc(C=O)cc12
Reactant: O=C1CSC(NC2CC2c2ccc(F)cc2)=N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccnc2ccc(/C=C3\SC(NC4CC4c4ccc(F)cc4)=NC3=O)cc12

Procedure:
The similar procedure as described in example 35 was used, starting with 4-ethoxy-quinoline-6-carbaldehyde (example 3b), 2-[2-(4-fluoro-phenyl)-cyclopropylamino]-thiazol-4-one, sodium acetate and acetic acid to give 5-[1-(4-ethoxy-quinolin-6-yl)-meth-(Z)-ylidene]-2-[2-(4-fluoro-phenyl)-cyclopropylamino]-thiazol-4-one. LC-MS m/e 434.5 (MH+).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[Br:13]N1C(=O)CCC1=O.[CH3:21][O:22][C:23]([C:25]1[C:33]2[CH:32]=[C:31]([CH3:34])[O:30][C:29]=2[C:28]([O:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:27][CH:26]=1)=[O:24]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:22][C:23]([C:25]1[C:33]2[CH:32]=[C:31]([CH2:34][Br:13])[O:30][C:29]=2[C:28]([O:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:27][CH:26]=1)=[O:24]
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(C)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(CBr)cc12
Temperature: 25 °C
Yield: 5.8 %

Procedure:
To a well stirred refluxing solution of AIBN (500 mg) and N-bromosuccinimide (30.5 g, 0.171 moles) in carbon tetrachloride (500 mL) was added a Methyl-7-cyclopentyloxy-2-methylbenzo[b]furan-4-carboxylate (43.0 g, 0.151 moles) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and filtered thorough Celite bed. The filtrate was concentrated under vacuo to give product (3.1 g) as brown oil. The product obtained (50.0 g)was taken ahead for next step without further purification.
Reaction SMILES: CC([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13]C(C)=O)=[CH:5]1)=O.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Na+].[Cl-]>O>[OH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][CH:5]=1
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Oc1c[nH]c2ccccc12
Temperature: 85 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Indoxyl 1,3-diacetate (Sigma Chemical Co., St. Louis, Mo.) (10.0 g; 46.05 mmole) was suspended with stirring in thoroughly deoxygenated H2O (200 mL), maintained under an inert gas atmosphere. NaOH (16 g) was added at once and the reaction mixture was heated at ca. 85° C. for 15 min. The reaction was cooled in an ice/salt bath to <5° C., then dropwise treated with a thoroughly deoxygenated solution of citric acid monohydrate (30.63 g) in H2O (30 mL) at a rate that kept the reaction temperature <5° C. NaCl (30 g) was then added and the reaction stirred in the cold for 1 h. The greenish yellow solid product was collected by filtration with suction, washed with a minimum amount of deoxygenated, ice-cold aq 0.5 N citric acid and dried in vacuo overnight to give 3-hydroxyindole (4.94 g; 80%). This product was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[CH:26]([NH2:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:19].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[CH:26]([NH:31][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1)[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:19]
Reactant: CCOCCCNC(=O)C(N)CC(C)C
Reactant: CSc1nc(Cl)cc(COC2CCCCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(COC2CCCCC2)nc(SC)n1

Procedure:
A mixture of 4-chloro-6-cyclohexyloxymethyl-2-methylsulfanyl-pyrimidine, the hydrochloride salt of 2-amino-4-methylpentanoic acid (3-ethoxypropyl)amide (60 mg), and diisopropylethylamine (61 mg) in dimethylsulfoxide (0.5 mL) was heated at 95° C. for 16 h. The mixture was partitioned in water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (30% ethyl acetate in hexanes) to give 2-(6-cyclohexyloxymethyl-2-methylsulfanyl-pyrimidin-4-ylamino)-4-methyl-pentanoic acid (3-ethoxy-propyl)-amide (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.FC1C=C(C2N=CC(CCC(N3CCCCC3)=O)=CC=2)C=CC=1.[H-].[Na+].[C:47]([O:51][C:52](=[O:55])[CH2:53]Br)([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C>[C:47]([O:51][C:52](=[O:55])[CH2:53][NH:14][C:11]1[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccc(-c2ccc(F)cc2)nc1
Agent: O=C(CCc1ccc(-c2cccc(F)c2)nc1)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CNc1ccc(-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 300 mg (1.59 mmol) of 6-(4-fluoro-phenyl)-pyridin-3-ylamine (prepared analogously as described in Example 76(a) and (b)) and 104 mg (2.39 mmol) of sodium hydride (55% in mineral oil) in DMF were stirred at room temperature for 30 min. Then 466.4 mg (2.39 mmol) of bromoacetic acid tert-butyl ester were added and the reaction mixture was stirred for 2 h at room temperature and for 5 h at 100° C. After evaporation, water and ethyl acetate were added. The organic phase was separated, dried and evaporated. Yield: 480 mg.
Reaction SMILES: N(C[C@H]1CCNC[C@H]1O)=[N+]=[N-].C(N(CC)CC)C.FC1C([O:26][C:27]([C:29]2[N:30]=[N:31][C:32]([CH2:48][CH2:49][CH2:50][CH3:51])=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:37][CH:36]=3)[CH:34]=2)=O)=C(F)C(F)=C(F)C=1F.CCOC(C)=O>COCCOC>[CH2:48]([C:32]1[N:31]=[N:30][C:29]([CH:27]=[O:26])=[CH:34][C:33]=1[C:35]1[CH:36]=[CH:37][C:38]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:39][CH:40]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [N-]=[N+]=NC[C@H]1CCNC[C@H]1O
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCc1nnc(C=O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
To a solution of cis-4-azidomethyl-piperidin-3-ol (1.4 mmol, 272 mg) in DME (4.2 mL) was added triethylamine (5.62 mmol, 0.8 mL) and 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (1.41 mmol, 785 mg). Reaction was stirred at room temperature for 3 h. Upon completion, the reaction was quenched with 0.1N NaOH (40 mL), extracted, dried and removal of solvent afforded the residue which was chromatographed with hexane:EtOAc gradient to afforded (±)-cis-4-azidomethyl-3-hydroxy-piperidin-1-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (180 mg, 25% yield).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([N+:23]([O-])=O)[C:20]=1[NH:21][CH3:22])[C:14]([O:16][CH3:17])=[O:15].[CH:26]1([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[C:31]2[CH:39]=O)[CH2:28][CH2:27]1>O.C(O)C.C(Cl)Cl>[CH:26]1([CH2:29][N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[CH:32]=[C:31]2[C:39]2[N:21]([CH3:22])[C:20]3[C:11]([O:10][CH3:9])=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][C:19]=3[N:23]=2)[CH2:27][CH2:28]1
Reactant: CNc1c(OC)cc(C(=O)OC)cc1[N+](=O)[O-]
Reactant: O=Cc1cc2cccnc2n1CC1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1cc(OC)c2c(c1)nc(-c1cc3cccnc3n1CC1CC1)n2C
Temperature: 100 °C
Yield: 80 %

Procedure:
A solution of sodium hydrosulfite (512 mg, 2.498 mmol) in water (3.25 mL) was added to a solution of methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate (200 mg, 0.833 mmol) and 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (167 mg, 0.833 mmol) in ethanol (6.5 mL) in a microwave vial. The reaction mixture was heated in the microwave for 5 h at 100° C. The reaction mixture was diluted with DCM (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product as a colourless oil. The crude product was purified by column chromatography on a silica cartridge (25 g) using a gradient of 60% EtOAc/cyclohexane→100% EtOAc/cyclohexane. (The product eluted near the solvent front). The appropriate fractions were combined and evaporated under vacuum to give the product as a yellow oil—methyl 2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylate (260 mg, 0.666 mmol, 80% yield)
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH:25]=[CH:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:31][NH:32][CH3:33]>CO>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:30])[CH2:25][CH:26]([N:32]([CH3:33])[CH3:31])[CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCCC=CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: CNC
Solvent: CO
Product: CCCC(CC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)N(C)C
Yield: 34 %

Procedure:
N-cyclopropyl-N-(1-hex-2-enoyl-piperidin-4-yl)-3-trifluoromethyl-benzenesulfonamide (30) (250 mg, 0.56 mmol) and dimethylamine in methanol (2M, 3 mL) were heated in a sealed React-vial at 120° C. for 24 hours. The cooled solution was evaporated to dryness in vacuo and the residue chromatographed over flash silica eluting with ethyl acetate (3× column lengths) followed by ethyl acetate:methanol:ammonia (100:10:1) to give the title compound 44 (150 mg, 34%) as a white solid. TLC (SiO2, ethyl acetate: methanol: ammonia, 100:10:1) Rf=0.15 (UV detection, Dragendorff's reagent). LC: 100%. MS: m/z=490.3, 491.2 (M+H). 1H NMR (400 MHz, CDCl3): (1:1 mixture of rotamers) δ 8.14 (1H, s), 8.07 (1H, d, J=8 Hz), 7.88 (1H, d, J=8 Hz), 7.70 (1H, t, J=8 Hz), 4.74 (1H, d, J=12 Hz), 4.07 (1H, m), 3.95 (1H, d, J=12 Hz), 3.05 (2H, m), 2.50 (2H, m), 2.24 (6H, s), 2.15 (1H, 2d), 1.96 (1H, m), 1.86-1.69 (3H, m), 1.58-1.24 (6H, m), 0.98 (1H, m), 0.90 (3H, t, J=8 Hz), 0.87-0.75 (3H, m).
Reaction SMILES: C([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)N.C[N:14](C)[CH:15]=[O:16].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[C:5]12[C:4](=[N:12][CH:11]=[CH:10][CH:9]=1)[NH:14][C:15](=[O:16])[O:8][C:6]2=[O:7]
Reactant: NC(=O)c1ncccc1C(=O)O
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: O
Product: O=c1[nH]c2ncccc2c(=O)o1
Reaction time: 1 h

Procedure:
A 100 ml. flask was charged with 2.0 g. 2-carbamylnicotinic acid* suspended in 20 ml. dimethylformamide. A 5.5 g. portion of lead tetra-acetate was added to the suspension, and the mixture was stirred at 50°-60° for 1 hour. The reaction mixture was poured into 20 ml. water; solids were separated by filtration, and 3-azaisatoic anhydride was recrystallized from dioxane, and dried in vacuo for 2 hours. The final yield of 3-azaisatoic anhydride amounted to 1.48 g., melting point 217°-219°, and represented 75 percent of theory. The structure was confirmed by elemental analysis and infrared spectroscopy.
Reaction SMILES: [CH:1]12[CH:14]=[CH:13][CH:5]([CH:6]3[C:11](=[O:12])O[C:8](=[O:9])[CH:7]31)[CH:4]1[CH:2]2[CH2:3]1.[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16].O>C(O)(=O)C>[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:8](=[O:9])[CH:7]3[CH:6]([CH:5]4[CH:13]=[CH:14][CH:1]3[CH:2]3[CH:4]4[CH2:3]3)[C:11]2=[O:12])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2C3C=CC(C4CC34)C2C(=O)N1c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
250 g of tricyclo-[3.2.2.02.4 ]-non-8-ene-6,7-dicarboxylic acid anhydride (prepared from cycloheptatriene and maleic acid anhydride, K. Alder, Ber. 86, 1528-39 (1953)) and 200 g of 4-nitroaniline are refluxed in 1500 ml of glacial acetic acid for 3 hours. The reaction mixture cooled to 60° C is poured into 2000 ml of hot water, whereupon the crude product precipitates. After cooling, the crude product is filtered off, dried, and recrystallised from ethyl acetate; M.P. 210°-212° C.
Reaction SMILES: CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:21][CH:20]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[CH:21][CH:20]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reaction time: 0.33 h

Procedure:
A 1.0 M ZnCl2 solution in Et2O (5.40 mL, 5.40 mmol) was added cautiously to a stirred suspension of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.03 g, 4.72 mmol) in 1:1 t-BuOH:DCE (200 mL) at room temperature. After stirring for 20 minutes, tert-butyl 4-aminobenzylcarbamate (A11) (1.00 g, 4.50 mmol) was added followed by Et3N (752 μL, 5.40 mmol) and the resulting mixture stirred at room temperature overnight. The volatiles were removed in vacuo and the resulting tan solid was suspended in water (500 mL). The suspension was sonicated for 10 minutes, filtered and the filter cake was washed with water (2×100 mL) then dried under high vacuum to give the title compound A12 as a tan solid (1.77 g, 97%); 1H NMR (400 MHz, d6-DMSO) δ 10.63 (s, 1H), 8.79 (s, 1H), 7.61 (d, J=8.1 Hz, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 4.10 (d, J=6.0 Hz, 2H), 1.40 (s, 9H). LCMS-A: rt 6.356 min; m/z 401 [M−1]−.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[C:14]([N:15]([CH2:20][CH2:21][CH3:22])[C:16](=O)[CH2:17][CH3:18])=[CH:13][C:12]([CH3:23])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[O:35][CH3:36])[N:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[C:14]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][CH3:22])=[CH:13][C:12]([CH3:23])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[O:35][CH3:36])[N:10]=1
Reactant: CCCN(C(=O)CC)c1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CCC)c1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A 1M solution of LiAlH4 in THF (0.52 ml, 0.52 mmol) at 0° C. is added to a solution of N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-N-propyl-propionamide (94) (0.11 g, 0.26 mmol) in THF (1 ml). The mixture is stirred at 0° C. for 30 minutes and at room temperature for 15 hours. The reaction is quenched by ether containing water (5 ml) at 0° C. Water (1 ml) and EtOAc (20 ml) are added to the mixture and the suspension is stirred at room temperature for 20 minutes. MgSO4 (2 g) and Celite (2 g) are added and the mixture is stirred at room temperature for 40 minutes. The inorganic salts are removed and washed with EtOAc. The combined filtrates are concentrated under reduced pressure and the residue is purified by flash column chromatography to give [2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-dipropyl-amine (93); Rf (hexane/EtOAc=9:1)=0.39, MS m/z 413.4 (M+H) and [2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propyl-amine; Rf (hexane/EtOAc=9:1)=0.35, MS m/z 371.3 (M+H) (94)
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude product from Step A dissolved in 150 mL of anhydrous THF was added 50 mL of a 1.0M solution of lithium aluminum hydride in THF at 0° C. under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction was then quenched by sequential addition of 1.90 mL of water, 1.90 mL of 15% aqueous sodium hydroxide, and 5.70 mL water. The granular aluminum salts were separated from the reaction mixture by vacuum filtration through Celite, then the filtrate was evaporated in vacuo. The residue was redissolved in methylene chloride, dried (MgSO4), filtered, and evaporated. Removal of the residual solvent in vacuo afforded 20.290 g (80% two steps) of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>Cl>[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Product: CN(C)C1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
Dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine hydrochloride (10.5 g, 35.2 mmole) was dissolved in 7.5N hydrochloric acid (36 ml) and stirred for 96 hours at room temperature. After completion of the hydrolysis the reaction mixture was extracted with diethyl ether (2×50 ml). The aqueous phase was made alkaline with 5N sodium hydroxide solution while cooling with ice, extracted with dichloromethane (3×50 ml) and concentrated by evaporation. 4-dimethylamino-4-phenylcyclohexanone (Ket-1) was thus obtained as a yellow solid with a melting point of 1040-108° C. in a yield of 97% (7.4 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4F)c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccccc1-c1cccc2[nH]c3c(c12)CCN(Cc1ccccc1)CC3
Yield: 63.1 %

Procedure:
A solution of lithium aluminum hydride (0.25 g, 6.59 mmol) in tetrahydrofuran (5.0 mL) and a solution of 3-benzoyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.247 g, 0.642 mmol) in tetrahydrofuran (5.0 ml) were reacted in a manner similar to Example 1 to give 0.15 g (63%) of the title compound as pale yellow crystals: mp 157-159° C.; 1H NMR (400 MHz, CDCl3) δ 7.86, 7.37-7.24, 7.18-7.10, 6.91, 3.72, 3.00-2.90, 2.75-2.61, 2.57-2.48, 2.42-2.33; 13C NMR (100 MHz, CDCl3) δ 161.9, 159.4, 137.6, 135.3, 132.5, 130.0, 129.3, 128.7, 128.0, 127.5, 127.0, 124.1, 122.4, 121.0, 115.7, 115.4, 114.1, 110.7, 62.0, 56.1, 53.9, 28.8, 24.9; IR (drift) 3405, 2887, 2811, 1485, 1453, 1418, 1346, 1335, 1221, 1121, 924, 817, 782, 757, 740 cm−1; MS (EI) m/z 370 (M+); Anal. Calcd for C25H23FN2: C, 81.05; H, 6.26; N, 7.56. Found: C, 80.82; H, 6.35; N, 7.47.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]([CH2:26][CH2:27][CH2:28]Cl)=[O:25]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:28][CH2:27][CH2:26][C:24]([C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)=[O:25])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: O=C(CCCCl)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCC(=O)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 51 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 2-naphthyl ketone (3.5 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue dissolved in chloroform. Insolubles are filtered off. The filtrated is concentrated and the residue is purified by silica gel column chromatography [Kieselgel 60, eluant: benzene-ether (10:1)] and the product is recrystallized from ethanol to obtain 1-methyl-5-[3-(2-naphthoyl)propyl]thio-1,2,3,4-tetrazole (yield 51%) as colorless prisms, m.p. 118°-120° C.