Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([F:16])[CH:5]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>O1CCCC1>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[CH:28][C:29]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([F:16])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:9]=2[F:10])=[O:30])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CS(=O)(=O)Nc1cc(F)c(CN)cc1F
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C=CC(=O)NCc2cc(F)c(NS(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.6 %

Procedure:
To the 25 ml round bottom flask were put N-(4-aminomethyl-2,5-difluoro-phenyl)-methanesulfonamide hydrochloride (125 mg, 0.46 mmol), 3-(4-t-butylphenyl)acrylic acid (1.2 eq, 112 mg), and DMTMM (1.2 eq, 152 mg). And to this mixture was poured 15 ml tetrahydrofuran and stirred 12 hours at room temperature. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed 1N HCl solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was purified with column chromatography (n-hexane/ethyl acetate=1/1) to yield a solid (147 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[NH:36][C:37]([NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[F:47])=[O:38])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([C:26]([O:28]C(C)(C)C)=[O:27])[CH2:22]3)=[O:16])[S:14][C:7]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[NH:36][C:37]([NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[F:47])=[O:38])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]3)=[O:16])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCC(C(=O)OC(C)(C)C)C5)sc34)cc2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCC(C(=O)O)C5)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate (40 mg, 0.060 mmol) in 5 ml of methylene chloride was added 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours, and evaporated to dryness under reduced pressure. 5 ml of water was added to the residue, and the mixture was neutralized to pH=7 with saturated NaHCO3 solution with vigorous stirring. The precipitates were filtered, washed with 5 ml of water, and dried in vacuo to give 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylic acid as light brown solid. Yield: 37 mg, 100%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][N:13]3[C:14](=[O:20])[C:15]([CH2:18][OH:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:25]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:22]=[CH:21][N:13]3[C:14](=[O:20])[C:15]([CH2:18][O:19][CH3:25])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=c1c(CO)cnc2cc(C#Cc3cccc(F)c3)ccn12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Reaction time: 0.25 h

Procedure:
To a solution of 8-((3-fluorophenyl)ethynyl)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (16 mg) in anhydrous THF (5 mL) was added NaH (16 mg, 60% in oil) in portions. After the reaction mixture was stirred for 15 min, MeI (0.05 mL) was added. The solution was stirred for 30 min. Then the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the desired product (11 mg), which was purified by preparative HPLC. MS (ESI): 309 (MH+); 1H NMR (300 MHz, CD3OD) δ 9.07-9.05 (d, J=6.81 Hz, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.51-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.29-7.27 (m, 1H), 4.53 (s, 2H), 3.54-3.50 (d, J=7.02 Hz, 3H). mGluR5 PAM EC50: +++.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C@H:4]([C:12](O)=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.II.[OH-].[K+]>O1CCCC1.ClCCl>[NH2:3][C@H:4]([CH2:12][OH:13])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@H](CO)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 118.4 %

Procedure:
To a suspension of sodium borohydride (16.5 g) in dry tetrahydrofuran (600 mL), (L)-phenylalanine (30 g) was added at one portion. The flask was cooled to 0° C. under nitrogen atmosphere. Iodine (46.18 g) solution in tetrahydrofuran (150 mL) was added slowly in drop-wise manner over 40 minutes, resulting in vigorous evolution of H2. After the complete addition of iodine, the reaction mixture was heated to reflux for 18 hours and cooled to room temperature. The reaction mixture was quenched with methanol until the reaction mixture became clear. Further, the solution was stirred for 30 minutes at room temperature. The solvents were removed by rotary evaporation to obtain a white paste which was dissolved by 20% aqueous potassium hydroxide (450 mL). The solution was stirred for 4 hours and then dichloromethane was added. The organic layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure to afford 32.5 g of (L)-phenylalaninol as a viscous liquid. The crude product was used as such for the next step.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([C:18]2[CH2:23][CH2:22][O:21][CH2:20][CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(C2=CCOCC2)nc1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C2CCOCC2)nc1Cc1ccccc1
Yield: 42.2 %

Procedure:
20 mg of 10% palladium carbon was added to a mixture of 197 mg of 2-benzyl-6-(5,6-dihydro-2H-pyran-4-yl)-3-methoxymethyloxypyridine and 3 ml of ethanol, followed by stirring at room temperature overnight in a hydrogen atmosphere. After the atmosphere in the reaction system was replaced by nitrogen, the reaction solution was filtered through Celite. The solvent was removed, and then the residue was subjected to silica gel column chromatography using 20% ethyl acetate/hexane, to give 83.7 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S(Cl)([Cl:15])=O.Cl>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:15])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Cl)c1
Yield: 99.7 %

Procedure:
A solution of trans-3-chlorocinnamic acid (25.5 g) and thionyl chloride (33.6 g) in dry benzene (300 ml) was heated at reflux until the evolution of HCl and SO2 had ceased. Excess thionyl chloride and benzene were removed by distillation under reduced pressure to give trans-3-chlorocinnamoyl chloride (28 g) as an oil. A solution of trans-3-cinnamoyl chloride (4.0 g) in dry toluene (75 ml) was added with stirring to a solution of pyrrolidine (4.3 g) in dry benzene (75 ml) at ambient temperature. The reaction mixture was allowed to stir for 10 hr., after which time excess pyrrolidine and solvents were removed under reduced pressure. The residue was triturated with water, filtered, and recrystallized from ethanol/water as follows: the wet solid was dissolved in warm (40 - 45° C) ethanol (90 ml), the resulting solution filtered, and water (ca. 900 ml) added giving crystalline trans-1-(3-chlorocinnamoyl)pyrrolidine, m.p. 137 - 138° C. Elemental analysis, NMR, and IR spectra are consistent with the assigned structure.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:5]=1.[OH-].[Na+]>>[N:20]1([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([OH:25])=[O:2])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(N2CCCC2)c(Oc2ccccc2)c([N+](=O)[O-])c1

Procedure:
50 g of 3-(1-pyrrolidinyl)-4-phenoxy-5-nitrobenzoic acid methyl ester (preparation cf. Example 34, step (b) are saponified under heating with dilute sodium hydroxide solution.
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([CH:31]=[O:32])=[C:29]([CH:33]([CH3:35])[CH3:34])[CH:28]=[C:27]3[C:22]=2[C:23](=[O:38])[CH2:24][C:25]([CH3:37])([CH3:36])[O:26]3)=[CH:17][CH:16]=1.FC1C=CC(C2C(C=O)=C(CCC)C=C3C=2C(=O)CC(C)(C)O3)=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]([CH:31]([OH:32])[C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)=[C:29]([CH:33]([CH3:34])[CH3:35])[CH:28]=[C:27]3[C:22]=2[C:23](=[O:38])[CH2:24][C:25]([CH3:36])([CH3:37])[O:26]3)=[CH:17][CH:16]=1
Reactant: FC(F)(F)Oc1ccc([Mg]Br)cc1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Agent: CCCc1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC(C)(C)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Reaction time: 0.75 h

Procedure:
At −78° C., 2.35 ml (1.19 mmol) of a freshly prepared 0.5 M solution of bromo[4-(trifluoromethoxy)phenyl]magnesium in tetrahydrofuran are slowly added dropwise to a solution of 338 mg (990 μmol) of a 2:1 mixture of rac-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 20A) and rac-5-(4-fluorophenyl)-7-n-propyl-2,2-dimethyl-4-oxochroman-6-carbaldehyde in 8 ml of tetrahydrofuran. The mixture is then allowed to thaw slowly to −20° C. and stirred at this temperature for 45 min. 10% strength sodium bicarbonate solution is then added, the mixture is extracted three times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, the solvent is then removed under reduced pressure and the residue is purified by preparative HPLC (method 1).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:19]=2)[CH2:13]1)C1C=CC=CC=1>[Pd].CCO>[NH2:10][CH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=3)[N:21]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[OH:35])[N:19]=2)[CH2:13]1
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 3 h

Procedure:
To a mixture of benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (610 mg, 1.26 mmol) and EtOH (15 mL) in a round bottom flask was added Pd/C (61 mg, 10% wt Pd on carbon) and the flask was sealed with a septum. The atmosphere in the flask was evacuated, purged with N2, and equipped with a balloon charged with H2. The mixture was then stirred under an H2 atmosphere at ambient pressure for 3 h. After filtration through a plug of Celite, using MeOH as the eluting solvent, the reaction mixture was concentrated to a yellow solid 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (441 mg). LC/MS: m/z 349.3 (M+H)+ at 1.52 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.45 (m, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.64 (s, 1H), 7.35-7.39 (m, 2H), 6.92-6.96 (m, 2H), 4.52 (d, J=12.5 Hz, 1H), 4.41 (d, J=13.2 Hz, 1H), 3.26-3.29 (m, 2H), 3.02-3.08 (m, 1H), 2.55-2.61 (m, 1H), 2.45-2.48 (m, 1H), 1.84-1.91 (m, 2H), 1.65-1.77 (m, 3H), 1.24-1.36 (m, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1)(C(C)(C)C)(C)C>C(O)(=O)C.O>[OH:8][CH2:9][CH2:10][C@H:11]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:15]=2[CH2:14][CH2:13][O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1ccc2c(c1)CCO[C@H]2CCO
Reaction time: 2 h

Procedure:
(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide (1 g, 2.98 mmol) was dissolved in a mixture of acetic acid (10 mL) and water (5 mL), then stirred for 2 h. The solution was evaporated to give a residue that was dried in vacuo at 55° C. to give the title compound as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.O.[ClH:34]>>[ClH:34].[S:29]1[CH:30]=[CH:31][C:27]([C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:7]4[CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:15][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28]1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Agent: Cl
Solvent: O
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ccsc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 20 mL vial which contained a solution of the product from step 1 (155 mg, 0.35 mmol) in HCl (4 N in dioxane 4 mL) was added water (0.5 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 24 h. The solvent was removed to yield the crude which was purified by recrystallization from THF-ether to afford the title product (125 mg, 75%); LCMS; 100%, APCI+, Calcd: 435.6; Found m/z: 436.5, (M+1); 1H NMR (400 MHz, DMSO-d6); δ 1.74-2.08 (m, 5H), 2.15-2.26 (m, 1H), 2.31-2.40 (m, 2H), 3.05-3.20 (m, 2H), 3.40-3.49 (m, 1H), 3.53-3.63 (m, 1H), 3.83-3.93 (m, 1H), 3.90 (s, 2H), 4.15-4.19 (m, 1H), 4.27 (dd, J1=10.8 Hz, J2=3.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.51 (dd, J1=4.8 Hz, J2=1.6 Hz, 1H), 7.60-7.63 (m, 3H), 7.79 (dd, J=2.8 Hz, J2=1.2 Hz, 1H):
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19](Br)=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(OCC)C>[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([C:23]4([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1
Reactant: CN1CCC(c2cc3cc(Br)ccc3o2)CC1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1CCC(c2cc3cc(C4(O)CCCCC4)ccc3o2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
480 ml of a 1.35 N solution of n-butyl lithium in abs. diethyl ether is added dropwise within 30 minutes at -5° to a solution of 60 g of 1-methyl-4-(5-bromo-2-benzofuranyl)-piperidine [cp. Example 19] in 300 ml of diethyl ether. The reaction temperature during the dropwise addition is maintained at between -50° and 0° by external cooling. The solution is afterwards stirred for a further 90 minutes at 5° to 10°. There is then added dropwise within 30 minutes a solution of 85 ml of cyclohexanone in 100 ml of abs. diethyl ether, with the reaction temperature being kept at 0° to 5° by external cooling. The reaction solution is subsequently stirred for 15 hours at room temprature, and then poured, with stirring, onto 300 g of ice, and the aqueous phase extracted three times with 500 ml of ethyl acetate each time. The combined organic extracts are dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 300 ml of 2 N hydrochloric acid, and the acid solution washed with ether. The aqueous solution is then adjusted by addition of 10% sodium hydroxide solution to pH 12, and extracted with 1000 ml of chloroform. The chloroform solution is dried with sodium sulphate, filtered off, and concentrated by evaporation to obtain crude 1-methyl-4-[5-(1-hydroxycyclohexyl)-2-benzofuranyl]-piperidine. The free base melts at 155° to 157° after recrystallisation from cyclohexane. The hydrochloride is prepared with hydrogen chloride in ethyl acetate, and recrystallised from acetone, whereupon it melts at 226°-229°.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[Li+].[Cl-].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[O:29]>C1COCC1>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:28]([OH:29])[C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=4)=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate (150 mg, 0.44 mmol) was dissolved in THF (1.3 mL, 3 mL/mmol) and the solution was cooled to 0° C. A solution of TMPMgCl/LiCl (1 M in toluene/THF, 1.6 equiv., 0.704 mL, 0.70 mmol) was added down the side of the vial slowly. The mixture was allowed to stir for 30 minutes. After 30 minutes, 3-(trifluoromethyl)benzaldehyde (1.0 equiv., 0.06 mL, 0.44 mmol) was added and the reaction continued to stir for 30 minutes. The reaction was quenched with saturated NH4Cl and extracted 3 times with methylene chloride. The organic layers were combined, dried with Na2SO4 and concentrated. The crude was purified by flash chromatography to afford 73 mg (32.2% yield) of a white solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.C(P(CCCC)CCCC)CCC.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([CH2:41][CH2:42]O)=[CH:39][CH:38]=1)([O-:36])=[O:35].CCOC(/N=N/C(OCC)=O)=O.[NH4+].[Cl-]>C(Cl)Cl>[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([CH2:41][CH2:42][N:11]2[CH2:10][CH:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[CH:39][CH:38]=1)([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CCN2CC=C(c3ccccc3)CC2)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
1.29 g (6.6 mmole) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride, 0.92 ml (6.6 mmole) of Et3N and 1.62 ml (6.6 mmole) of tributylphosphine are added to a solution of 1.0 g (5.98 mmole) of 4-nitrophenethyl alcohol in 25 ml of CH2Cl2. The reaction mixture is agitated vigorously at 23° C. and 1.04 ml (6.6 mmole) of diethylazodicarboxylate is added dropwise. After 4 hours, the reaction is stopped by adding 5 ml of a saturated solution of NH4Cl. After decantation, the aqueous phase is extracted twice with 5 ml of CH2Cl2, the organic phases are combined and washed twice with 5 ml of water, twice with 5 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified on a silica column (eluent Heptane/AcOEt: 9/1 to 7/3) in order to produce 1.20 g of the expected product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.S(Cl)(Cl)=O.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]O.C(N(CC)CC)C>C(#N)C>[NH:1]1[CH:5]=[C:4]([C:6]2[O:8][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)[N:3]=[CH:2]1
Reactant: O=C(O)c1c[nH]cn1
Reactant: CC(C)(N)CO
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2c[nH]cn2)=N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
4-Imidazolecarboxylic acid (2 grams, 17.9 mmol) and thionyl chloride (5 mL, 68.5 mmol) were heated to reflux in anhydrous acetonitrile (50 mL) under nitrogen for 1 hour. Then all volatile was removed under vacuum. The conversion to acid chloride is almost quantitative. To a solution of imidazole acid chloride in anhydrous acetonitrile (10 mL) was added dropwise a solution of 2-amino-2-methyl-1-propanol) (2.1 g, 21.4 mmol) and triethylamine (3.0 mL, 21.4 mmol) in anhydrous acetonitrile (10 mL) at 0° C. under N2. After the addition, the ice-bath was removed and the mixture was stirred at room temperature for 5 hours. The white solid of triethylamine hydrochloride was filtered out. Solvent and excess aminoalcohol were removed under vacuum. Dark brown oil was obtained. The dark brown oil was dissolved in hot acetonitrile (20 mL). After the solution was cooled down, a solution of thionyl chloride (5 mL) in anhydrous acetonitrile (10 mL) was added dropwise at 0° C. After stirring at room temperature for 2 hours, all volatile was removed under vacuum. To the oily residue was added acetonitrile (20 mL) and 10% aqueous potassium carbonate solution (20 mL). The mixture was heated to reflux for 2 hours. Two layers were observed after the mixture was cooled down. The water layer was discarded. Sodium bicarbonate solution was added to the organic layer, and the resulting mixture was extracted with ethyl acetate 3 times. After drying over magnesium sulfate and removal of solvent, flash chromatography (ethyl acetate:methanol=4:1) yielded pure 2-(imidazol-4-yl)-4,4-dimethyloxazoline as brown oil (1.75 g, 60%). 1H NMR (acetone-d6) δ1.35 (s, 6H), 4.10 (s, 2H), 7.58(s, 1H), 7.85(s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[C:20]([NH2:21])=[N:19][C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[CH:17][C:12]=2[CH:11]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[C:10]([C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:20]([NH:21][C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:19][C:13]=2[N:14]=1
Reactant: Cc1cc(C)c(-c2cc3cnc(N)nc3nc2N)c(C)c1
Reactant: CC(C)(C)N=C=O
Product: Cc1cc(C)c(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c(C)c1

Procedure:
The title compound was prepared from 0.25 g of 6-(2,4,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 96 and 0.109 mL of tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with 1:1 CHCl3 :EtOAc; mp 281-297° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 379 (MH+ +1, 100), 380 (MH+ +2, 23).