Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N+:4]([O-:16])[CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N+:4]([O-:16])[CH:3]=1
Reactant: O=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c2cc(F)c[n+]3[O-])CC1
Yield: 66 %

Procedure:
A mixture of (7-fluoro-5-oxido-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (as the methyl hemiacetal) (327 mg, 1.286 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (283 mg, 1.1 eq.) in chloroform:methanol (9:1 v:v) (5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (481 mg, 2 eq.). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (5 ml). The reaction was then diluted with DCM (80 mL) and the organic phase was separated using a hydrophobic frit. The aqueous phase was extracted with DCM (2×50 mL) The combined organic extracts were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% (2M NH3 in MeOH)/DCM gradient to provide the desired compound (345 mg, 66%) as a tan foam.
Reaction SMILES: CON1CCN(C2C=CC=CC=2)CC1.C1(CC(O)=O)C2C=CC=CC=2CCCO1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=O)[CH2:45][CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.[ClH:58]>CCOCC.CO>[ClH:58].[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH:46]3[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[CH2:50][CH2:49][CH2:48][O:47]3)[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(N2CCN(C(=O)CC3OCCCc4ccccc43)CC2)cc1
Agent: CON1CCN(c2ccccc2)CC1
Agent: Cl
Agent: O=C(O)CC1OCCCc2ccccc21
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(N2CCN(CCC3OCCCc4ccccc43)CC2)cc1

Procedure:
Step 5--Following the general procedure of EXAMPLE 50 and making non-critical variations p-methoxyphenylpiperazine is acylated with (1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)acetic acid (CXXIII, 619 mg) and the resulting amide, 1-(4-methoxyphenyl)-4-(1,3,4,5-tetrahydrobenzo[c]oxepin-1-yl)acetyl piperazine (CXXIV, 1.07 g) is reduced according to the general procedure described in EXAMPLE 50 (making non-critical variations) to give crude product. This crude material is dissolved in ether (30 ml) and methanol (3 ml) and treated with gaseous hydrochloric acid resulting in the formation of a salt. This crude salt is recrystallized from methanol/ethyl acetate to give the title compound, mp 217.0-219.0° (uncorrected, decomp).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:21])[CH3:15])[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
20 g (106 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 12 ml (116 mmol) of 2,4-pentanedione, 9.1 ml (159 mmol) of acetic acid and 0.21 ml (2.1 mmol) of piperidine in 400 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from isopropanol. 24.3 g (73% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[CH2:7][N:8]1[C:12]([CH:13]([F:15])[F:14])=[N:11][N:10]([CH3:16])[C:9]1=[O:17].[CH3:20][C:21]([OH:25])([C:23]#[CH:24])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.COC(C)(C)C.C(#N)C>[F:14][CH:13]([F:15])[C:12]1[N:8]([CH2:7][C:6]2[CH:18]=[C:2]([C:24]#[C:23][C:21]([OH:25])([CH3:22])[CH3:20])[CH:3]=[CH:4][C:5]=2[CH3:19])[C:9](=[O:17])[N:10]([CH3:16])[N:11]=1
Reactant: C#CC(C)(C)O
Reactant: Cc1ccc(Br)cc1Cn1c(C(F)F)nn(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Cc1ccc(C#CC(C)(C)O)cc1Cn1c(C(F)F)nn(C)c1=O
Temperature: 25 °C
Yield: 59.6 %

Procedure:
664 mg (2.0 mmol) of 4-(5-bromo-2-methylbenzyl)-5-difluoromethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 40), 1.00 g (11.9 mmol) of 2-methyl-3-butyn-2-ol, 70.2 mg (0.10 mmol) of PdCl2(PPh3)2, 57.1 mg (0.30 mmol) of copper iodide, 78.7 mg (0.30 mmol) of triphenylphosphine, 1.0 ml of triethylamine and 10 ml of acetonitrile were mixed, and the mixture was heated under reflux for 5 hours in nitrogen atmosphere. After cooling to room temperature, t-butyl methyl ether was added to the reaction solution, and the mixture was filtrated through celite, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=2/1 (v/v)) to obtain 400 mg of 5-difluoromethyl-4-{5-(3-hydroxyl-3-methyl-1-butynyl)-2-methylbenzyl}-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Compound 290).
Reaction SMILES: [CH2:1]=[O:2].[C:3](=O)([O-])O.[Na+].[Br-].C([NH:11][C@@H:12]1[C:47](=[O:48])[N:14]2[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40])=[C:16]([CH2:19][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:17][S:18][C@H:13]12)=O>C(Cl)Cl>[CH:1]([NH:11][C@@H:12]1[C:47](=[O:48])[N:14]2[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:44])([Cl:45])[Cl:46])=[O:40])=[C:16]([CH:19]=[CH2:3])[CH2:17][S:18][C@H:13]12)=[O:2]
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=C([O-])O
Reactant: C=O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 0.75 h

Procedure:
40% -Aqueous formaldehyde solution (4 ml.) and 4%-aqueous sodium hydrogen carbonate solution (6 ml.) were added to a vigorously stirred solution of [7β-formamido-4-(2,2,2-trichloroethoxycarbonyl)ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (357 mg., 0.5 mmole) in methylene chloride (20 ml.). The two-phase mixture was stirred for 45 minutes, and the organic phase was washed with 2N-hydrochloric acid and water (20 ml. of each), dried (MgSO4), and evaporated to an oil (0.35 g). this was subjected to preparative-layer chromatography on Kieselgel G (Merck PF254+366) using 20% acetone in methylene chloride as eluant to give the title ester as a cream foam (84 mg., 43.5%), λmax. (EtOH) 297.5 nm (ε 10,700), τ (CDCl3) 1.69 (1H, s; CHO), 2.81 (1H, dd, J 11.5 and 18 Hz; CH=CH2), 3.24 (1H, d, J 9 Hz; NH), 4.05 (1H, dd, J 9 and 4.5 Hz; C7 --H), 4.43 (1H, d, J 18 Hz) and 4.55 (1H, d, J 11.5 Hz) (CH=CH2), 4.90 (1H, d, J 4.5 Hz; C6 --H), 4.94 and 5.20 (2H, AB-q, J 12 Hz; CH2CCl3), 6.22 and 6.45 (2H, AB-q, J 18 Hz; C2 --H2).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([Mg]Br)=[CH:8][CH:7]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:15]2([OH:23])[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14]2)=[CH:8][CH:7]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A suspension of anhydrous cerium chloride (43.9 g, 178.0 mmol) in THF (250 mL) was stirred at room temperature for 2 hours under nitrogen. 4-Fluorophenylmagnesium bromide (75.6 mL of 2.0M solution in diethyl ether, 151.2 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (15.36 g, 116.4 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature overnight (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Unreacted 2-indanone was distilled off. The residue was subjected to Kugelrohr distillation (165° C./0.3 mm Hg). 2-(4-Fluorophenyl)-2-indanol (21.62 g) was obtained in pure form. 1 H-N.M.R. (CDCl3) d 2.22 (br s, 1H), d 3.24 (d, J=16.3 Hz, 2H), d 3.47 (d, J=16.3 Hz, 2H), d 7.04 (m, 2H), d 7.20-7.28(m, 4H), d 7.52(br d, J=9.0, 5.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:10][CH2:9][O:8][CH2:7][C:6]=2[CH:11]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:4]2[C:5]3[O:10][CH2:9][O:8][CH2:7][C:6]=3[CH:11]=[C:2]([F:1])[CH:3]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cc(F)cc2c1OCOC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cc(F)cc3c2OCOC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 6-fluoro-4H-benzo[1,3]dioxine-8-carboxylic acid (386 mg, 1.95 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (400 mg, 1.95 mmol), HATU (1.11 g, 2.93 mmol) in anhydrous DMF (8 mL) is added DIPEA (484 μL, 2.93 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (61) as white solid (720 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:1].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH2:13][O:14][CH3:15])[C:4]=23)[CH2:18]1
Reactant: COCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(=O)Nc1c[nH]c2ncc(Cl)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 215.3 %

Procedure:
(R)-tert-Butyl 1-(5-chloro-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.185 g, 0.422 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added. The reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-50 CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide hydrochloride (0.170 g, 98% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.10 (s, 1H), 7.41 (s, 1H), 4.09 (s, 2H), 3.71-3.68 (m, 1H), 3.49-3.46 (m, 1H), 3.40 (s, 3H), 3.27-3.13 (m, 3H), 2.11-2.08 (m, 1H), 1.78-1.75 (m, 1H), 1.67-1.65 (m, 1H), 1.54-1.50 (m, 1H). LCMS (APCI+) m/z 338 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:36])[C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[N:22]=2)[NH:17][CH:16]=1)=[O:14])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][C:9]1([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4C(=O)OC(C)(C)C)c3n2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCN4)c3n2)cc(OC)c1OC
Reaction time: 48 h
Yield: 63.1 %

Procedure:
To a solution of 2-methyl-2-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (18 mg, 0.04 mmol) in anhydrous dichloromethane (3.0 ml) was added trifluoroacetic acid (1.0 ml, 13.5 mmol) dropwise. The reaction mixture was stirred for two days. The reaction mixture was partitioned between EtOAc/saturated aqueous Na2CO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated. The residue was purified by preparative thin layer chromatography using 0.5:9.5:90 concentrated aqueous NH4OH: MeOH: dichloromethane as eluant to provide 10 mg (70%) of (2-methyl-pyrrolidin-2-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a light yellow solid. M+H=397.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([O:9]C)[CH:5]=[CH:4][C:3]=1[CH:11]([NH:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2)[C:12]([OH:20])([CH2:17][O:18]C)[C:13]([F:16])([F:15])[F:14].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH:11]([NH:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2)[C:12]([OH:20])([CH2:17][OH:18])[C:13]([F:16])([F:14])[F:15]
Reactant: COCC(O)(C(Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(OC)c(F)c1Cl)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1ccc2c(NC(c3ccc(O)c(F)c3Cl)C(O)(CO)C(F)(F)F)cc(F)cc2[nH]1
Reaction time: 16 h
Yield: 17.2 %

Procedure:
To 100 mg (0.20 mmol) of 5-{[1-(2-Chloro-3-fluoro-4-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-(methoxymethyl)propyl]amino}-7-fluoro-1H-quinolin-2-one of example 5 in 8.6 dichloromethane at −30° C. are added 1.6 ml of a 1 M solution of boron tribromide in dichloromethane under argon. The reaction mixture is stirred for 16 hours in a temperature range of between 0° C. and 25° C. The reaction mixture is mixed at 0° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate the batch is allowed to come to room temperature, stirred for 10 minutes and phases are separated. The aqueous phase is acidified with 4 M HCl and extracted with 10% methanol in dichloromethane. After removal of the solvent preparative thin layer chromatography on silica gel (ethyl acetate/methanol 4:1) yields 16 mg of the title compound.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15]([O:23][CH3:24])=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH:20]([C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=1)[O:23][CH3:24])([CH3:22])[CH3:21]
Reactant: COC(=C(C(C)C)C(C)C)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=C(C(C)C)C(C)C)c1cccc(O)c1

Procedure:
To a solution of 0.97 g (2.78 mmol) of alkene 1a in 30 ml of dry THF was added 0.81 g (1.1 eq.) of tetra-n-butyl-ammonium fluoride. After stirring for one hour TLC (silica, 20% ethyl acetate/hexane) showed complete conversion of starting material to a new compound. The THF was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate solution was extracted four times with water and dried. Silica gel (2 g) was added and the solvent evaporated. The material was purified by column chromatography on silica gel, eluting with 10-20% ethyl acetate/hexane yielding 0.568 g (87%) of 1b: 1H NMR (CDCl3) δ 7.5-6.5 (m, 4H), 4.91 (s, 1H), 3.20 (s, 3H), 2.47 (sept, 1H), 2.33 (sept, 1H), 1.25 (d, 6H), 0.92 (d, 6H); 13C NMR (CDCl3) δ 129.25, 124.98, 122.60, 116.54, 114.98, 114.56, 56.38, 30.52, 26.80, 22.11, 21.08; Mass spectrum (m/z): 234, 219, 191; exact mass, calc'd. 234.1620, found 234.1620.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:12][C:13]([NH:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14]>CS(C)=O>[CH3:8][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH2:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:33][CH:34]=1)=[O:14]
Reactant: Cc1ccccc1O
Reactant: O=C(CCl)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccccc1OCC(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 7.5 h
Yield: 43.8 %

Procedure:
o-Cresol (0.36 g) is dissolved in dimethylsulfoxide (4 ml) containing sodium hydroxide powder (0.18 g) and thereto is added 1-[4-(2-chloroacetylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.03 g). The mixture is stirred at 90° C. for 7.5 hours. The reaction mixture is poured into ice-water (300 ml) and the precipitated crystal is collected by filtration, washed with water, and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1), and recrystallized from ethyl acetate to give 1-{4-[2-(2-methylphenoxy)acetylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (546 mg) as colorless scales, m.p. 172.5-175° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.C(OC(OCC)[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])C.[CH2:29](Cl)Cl>O.C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][CH:16]=[C:17]2[CH:18]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH3:29]
Reactant: CCOC(CCCN1CCCCC1=O)OCC
Reactant: COc1ccc(NN)cc1
Reactant: ClCCl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]cc(C(C)N3CCCCC3=O)c2c1
Temperature: 80 °C

Procedure:
One heats to 80° C a solution consisting of 140 mls of water, 60 mls of acetic acid and 40 mls of normal hydrochloric acid. One then adds 5.52 g of p-methoxyphenylhydrazine followed by 9.7 g of 1-(4,4-diethoxybutyl)-2-piperidone. The solution is maintained at 80° C for 2 hours. It is then cooled to 5° C and then one adds 200 mls of water and 150 mls of methylene chloride. After decanting, the aqueous phase is extracted again with 200 mls of methylene chloride. The organic phases are combined, washed with 100 mls of water and then with a saturated solution of sodium bicarbonate, dried over sodium sulphate, filtered over bleaching charcoal and then evaporated to dryness under reduced pressure (20 mm of mercury). The residue (10 g ) is chromatographed over 75 g of silica gel contained in a column with a diameter of 2.7 cm and eluting with ethyl acetate, collecting fractions of 120 mls. Fractions 4 to 12 are evaporated. In this way one obtains 7.5 g of 1[1(5-methoxy-3-indolyl)-ethyl]2-piperidone melting at 150° C. 1-(4,4-diethoxy-butyl)-2-piperidone may be prepared in the following manner:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[CH3:31][S:32](O)(=[O:34])=[O:33]>O1CCCC1>[S:32]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)(=[O:34])(=[O:33])[CH3:31]
Reactant: CS(=O)(=O)O
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(C)(=O)=O)C[C@H]21
Temperature: 60 °C
Yield: 98 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, 10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.6 mmol) is dissolved in 9 ml of tetrahydrofuran. The solution is heated up to 60° C. 247 μg (3.8 mmol) of methanesulfonic acid are added. After crystallisation the suspension is stirred over night. The crystals are filtered off and dried to obtain 1.73 g (95%) of the title compound (m.p.: 193° C.).
Reaction SMILES: C[C:2]1([C:11]2[CH:16]=[CH:15][C:14](C(F)(F)F)=[CH:13][CH:12]=2)OC2C=CC=CC=2[O:3]1.[N+]([O-])(O)=[O:22].O>ClC(Cl)C>[O:22]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:2][O:3]1
Reactant: CC1(c2ccc(C(F)(F)F)cc2)Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Solvent: CC(Cl)Cl
Solvent: O
Product: c1ccc2c(c1)COO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 2-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-benzodioxole (5.6 g) in dichloroethane (15 ml) was added over 10 minutes to vigorously stirred nitric acid (50% w/v, 25 ml) keeping the temperature at 15°-20° C. by means of a cooling bath. The resulting reaction mixture was stirred for a further 1 hour at 20° C., poured into water (200 ml) and extracted with methylene chloride (3×100 ml). After drying over anhydrous sodium sulphate, the extract was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methylene chloride as eluant, affording the pure product benzodioxole as a pale yellow oil (5.3 g, 82%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][CH:30]([F:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[F:40][CH:30]([F:29])[C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: FC(F)c1nc2ccccc2[nH]1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure D, 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 was reacted with 2-(difluoromethyl)-1H-benzo[d]imidazole to give 157. 1H NMR (400 MHz, DMSO) δ 8.43 (d, J=8.3 Hz, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.00-7.72 (overlapping m, 3H), 7.51 (app t, J=7.7 Hz, 1H), 7.44 (app t, J=7.7 Hz, 1H), 4.56 (br s, 4H), 4.03 (s, 1H), 3.86 (br s, 4H), 3.74 (br s, 2H), 2.92 (d, J=10.6 Hz, 2H), 1.99 (t, J=11.3 Hz, 2H), 1.67 (d, J=11.8 Hz, 2H), 1.38-1.10 (overlapping m, 3H), 1.04 (s, 6H). LCMS: 538.3