Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=2)=[N:5][N:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C([Li])CCC>O1CCCC1>[CH3:13][C:9]1[N:8]=[C:7]([C:6]2[C:2]([B:17]([OH:22])[OH:18])=[C:3]3[CH2:16][CH2:15][CH2:14][N:4]3[N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccc(-c2nn3c(c2Br)CCC3)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2nn3c(c2B(O)O)CCC3)n1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 72.3 %

Procedure:
Place tetrahydrofuran (28.0 mL) in a 100 mL round-bottom flask equipped with a temperature probe, a magnetic stirrer, and a septum and put under a nitrogen atmosphere. Add 3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 1, 1.44 g, 5.18 mmol) and triisopropyl borate (3.10 mL, 13.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath. Add 1.4M n-butyllithium in hexanes (8.80 mL, 12.4 mmol) dropwise via a syringe pump over 10 min keeping the temperature below −40° C. Remove the dry ice/acetone bath and allow the reaction mixture to warm to room temperature. Add saturated aqueous ammonium chloride (10 mL) and extract with chloroform (2×1 00 mL). Combine the organic layers, dry over solid sodium chloride, and remove the solvent under reduced pressure to afford an oil. Purify the oil by normal phase flash chromatography (120 g Biotage KP-Sil 40 L: 100% ethyl acetate in hexanes for 25 min, 0-10% methanol in ethyl acetate in ramp over 15 min, then 10% methanol in ethyl acetate) to yield the title compound (910 mg, 73%). MS ES+ m/e 244 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([OH:20])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].[Cl:22][C:23]1[CH:28]=[C:27]([N+]([O-])=O)[CH:26]=[CH:25][N:24]=1>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:21])[NH:9][C@@H:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]([O:20][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=2)[CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccnc(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.32 g, 8.00 mmol) was suspended in dry DMF (15 mL) under argon. To this was added Intermediate 10a (1.05 g, 4.00 mmol) followed by 2-chloro-4-nitropyridine (0.64 g, 4.02 mmol). The dark coloured mixture was stirred at RT under argon for 30 min. The reaction mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated in vacuo. Purification by FCC, eluting with 0-70% ethyl acetate in cyclohexane, gave the title compound as a white foam (1.43 g, 95%). LCMS (Method 3): Rt 4.22 min, m/z 373.1 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([NH:27][C:28](N)=[O:29])([O-])=O>O.C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][NH:15][C:28]([NH2:27])=[O:29])([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Cc1cccc(NC2(CN)CCN(Cc3ccccc3)CC2)c1
Solvent: O
Solvent: CC#N
Product: Cc1cccc(NC2(CNC(N)=O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 48 h

Procedure:
A mixture of 1-benzyl-4-(3-methylphenylamino)-4-aminomethylpiperidine (247 m g, 0.79 mmol) and nitrourea (253 mg, 2.4 mmol) in mixture of acetonitrile (1 mL) and water (10 drops) was stirred at room temp. for 48 hrs. The resultant mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with a 1:1 mixture of 15% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:18]([F:21])([F:20])[F:19])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].OS([O-])(=O)=O.[Na+]>CO>[CH3:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:18]([F:19])([F:20])[F:21])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)c(-c2ccccc2)cc1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2ccccc2)c(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.6 g of methyl 2-methyl-4-phenyl-5-trifluoromethylbenzoate were dissolved in 100 ml of MeOH, 20 ml of a 1 N aqueous NaOH solution were added and the solution was stirred at RT for 8 h. The reaction mixture was poured onto 100 ml of a saturated aqueous NaHSO4 solution and extracted 3 times using 100 ml of EA each time. The organic phase was dried over Na2SO4 and the solvent was removed in vacuo.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH2:21][CH3:22]>C(OCC)(=O)C>[CH2:19]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCI
Reactant: CCOC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCNc1ccccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
A mixture of ethyl anthranilate (4.96 g, 30 mmol), potassium carbonate (13.8 g, 100 mmol), and n-butyl iodide (25 mL) was stirred at ambient temperature for 48 hours and refluxed for 8 hours. The cooled reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure and the residue obtained chromatographed eluting with ethyl acetate/hexane mixtures to afford the title comound as a light yellow liquid (2.2 g, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7](Cl)[C:8]3[N:9]2[C:12]([O:15][CH3:16])=[N:13][N:14]=3)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH:23]([NH2:26])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([NH:26][CH:23]([CH3:25])[CH3:24])[C:8]3[N:9]2[C:12]([O:15][CH3:16])=[N:13][N:14]=3)=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: COc1nnc2c(Cl)nc3ccc(Br)cc3n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nnc2c(NC(C)C)nc3ccc(Br)cc3n12
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 8-bromo-4-chloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline (2.0 g) in DMF (50 mL) was added solid sodium bicarbonate (1.1 g) and isopropylamine (0.82 mL). The resulting mixture was stirred at 23° C. for 18 hrs. and then diluted with EtOAc. The mixture was washed sequentially with water and brine, and then dried over sodium sulfate. Concentration afforded (8-bromo-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-isopropyl-amine as a light yellow solid. MS (M+H)+=337.3.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.O.[OH-].[NH4+]>C(O)C>[N:13]1([C:2]2[C:11]([CH3:12])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: Cc1cc2ccccc2nc1Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2ccccc2nc1-n1cncn1
Reaction time: 4 h
Yield: 70.9 %

Procedure:
A mixture of 1.78 g of 2-chloro-3-methyl-quinoline and 0.69 g of 1,2,4-triazole is melt and allowed to stand at 120° C. for 4 hours. The melt is cooled, then dissolved in 10 ml of ethanol, poured into 20 ml of water and neutralized with 1 ml of concentrated ammonium hydroxide. The precipitated product is filtered. Thus 1.49 g of the desired compound are obtained, yield 71%. Mp.: 80°-81° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.O>[CH2:12]([NH:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCOc1cccnc1
Reactant: NCc1ccccc1
Solvent: CO
Solvent: O
Product: c1ccc(CNCCCOc2cccnc2)cc1
Temperature: 120 °C
Yield: 2.2 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (0.65 g, 3.78 mmol) was dissolved in methanol (20 mL) and added to a mixture of benzylamine (13.5 mL) in water (20 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 120° C. (oil bath temperature) for 3 h. After cooling, the mixture was concentrated by rotary evaporation, and saturated NaCl solution (25 mL) was added to the residue. The mixture was acidified to pH 1 with 10% HCl solution and extracted with CHCl3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give a brown oil. The oil was concentrated by vacuum distillation to remove excess benzylamine (bp 85° C. at 15 mm Hg). The remaining residue (0.483 g) was purified by column chromatography on silica gel (25g) eluting with CH3OH—NH4OH (50:1, v/v). Fractions containing the product (Rf 0.39) were combined and concentrated on a rotary evaporator. The residue was re-chromatographed on silica gel (10 g). Fractions containing the product were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCL3 and the CHCL3 solution was dried (MgSO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 20 mg (2.2%) of a light-brown oil. The compound exhibits a Ki of 3000 nM. The compound exhibits neurotransmitter release of 29 percent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH3:19]>C(O)(C)C>[NH2:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1N
Temperature: 110 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (Example 1b, 796 mg, 3.0 mmol) and ammonia (25% aqueous solution, 10 mL) in isopropanol (40 mL) was stirred at 110° C. in a pressure reactor overnight. Most of the solvent was then removed under reduced pressure, and the reaction mixture was diluted with water. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as an off-white solid (680 mg, 92%). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=7.0 Hz, 3H), 3.88 (s, 3H), 4.32 (q, J=7.0 Hz, 2H), 7.36 (dd, J=2.8, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 8.23 (bs, 2H), 8.77 (s, 1H). MS 247 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([NH:17][CH3:18])=[CH:10][CH:9]=3.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:19](=[O:21])[CH3:20])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][C:11]([NH:17][CH3:18])=[CH:10][CH:9]=3
Reactant: CNc1ccc2c(c1)Sc1cc(NC)ccc1N2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CNc1ccc2c(c1)Sc1cc(NC)ccc1N2C(C)=O
Temperature: 120 °C
Yield: 53 %

Procedure:
The 3,7-dimethylamino-10H-phenothiazine obtained in Synthesis 1 was placed in a 250 cm3 round bottom flask and acetic anhydride ((H3CCO)2O, 40 cm3) and pyridine (10 cm3) were added, and the resulting solution was heated at 120° C. for 18 hours with stirring. The reaction mixture was cooled to room temperature and then poured carefully into ice-water while stirring to give a light brown solid, which was filtered using a standard Buchner funnel apparatus with a water aspirator, washed once with water (100 cm3), and dried in an oven at 60° C. for 3 hours to yield the title compound (MW 327.45, 4.63 g, 14.1 mmol, yield 53%), which was recrystallised from ethanol by dissolving it in hot ethanol (100 cm3), adding activated charcoal (1 g), filtering to remove the charcoal, cooling the solution to 5° C. using an ice-water bath so that a precipitate formed (colourless crystals), and filtering using a standard Buchner filter with a water aspirator in order to collect the crystals. The crystals where then dried in an oven at 60° C. for 3 hours.
Reaction SMILES: [Br-].[CH3:2][CH:3]([CH3:26])[CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=O)=[CH:41]2>C1COCC1>[Cl:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([CH:47]=[CH:6][CH2:5][CH2:4][CH:3]([CH3:26])[CH3:2])=[CH:41]2
Reactant: CC(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCC=Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of (4-methyl-pentyl)-triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes and then the solution of 5-chloro-1H-indole-2-carbaldehyde was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-(5-methyl-hex-1-enyl)-1H-indole was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH2:17][C:18]#[N:19])[CH:5]=[CH:4][N:3]=1.CO>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH2:17][C:18]#[N:19])[CH:5]=[CH:4][N:3]=1
Reactant: N#CCc1cc(F)ccc1C#Cc1ccnc(Cl)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#CCc1cc(F)ccc1CCc1ccnc(Cl)n1
Reaction time: 24 h
Yield: 54.7 %

Procedure:
2-(2-((2-Chloropyrimidin-4-yl)ethynyl)-5-fluorophenyl)acetonitrile (0.695 g, 2.56 mmol) is dissolved in ethyl acetate (90 ml), and 10% Pd/C (0.142 g, 0.133 mmol) are added. The suspension is hydrogenated at RT for 24 h under an H2 pressure of 40 psi in a Parr apparatus (hydrogenation apparatus). Since the reaction proceeds very sluggishly, 9 ml of methanol and further catalyst are added (10% Pd/C (0.142 g, 0.133 mmol). Over a further 28 h, 142 mg of catalyst are added three further times until complete conversion is observed. The dark suspension is filtered, washed with ethyl acetate and methanol, and the filtrate is evaporated to dryness in vacuo. Chromatography of the 700 mg of crude product on silica gel with petroleum ether/ethyl acetate=7:3 gives 386 mg of 2-(2-(2-(2-chloropyrimidin-4-yl)ethyl)-5-fluorophenyl)acetonitrile (1.400 mmol, 54.7% yield) as yellowish oil;
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[Br:14]Br.N([O-])=O.[Na+]>Br>[Br:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: BrBr
Reactant: Nc1cccc(-c2ccccc2)n1
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1cccc(-c2ccccc2)n1
Temperature: -20 °C
Yield: 80.1 %

Procedure:
48% HBr 50 mL was added to 6.9 g (40 mmol) of 2-amino-6-phenylpyridine and stirred. The solution was cooled down to −20° C., and 7.7 g (48 mmol) of bromine was dropwise added thereto. Further, 2.8 g (40 mmol) of sodium nitrite was dropwise added thereto. The solution was stirred for 3 hours while elevating the temperature up to room temperature. After finishing the reaction, the solution was extracted with ethyl acetate, and the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 7.5 g (yield: 80%) of 2-bromo-6-phenylpyridine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:14](=[O:34])[CH2:15][N:16]4[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][O:23][C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)[CH2:17]4)[CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH:14]([OH:34])[CH2:15][N:16]4[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][O:23][C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH2:17]4)[CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc3c(c2)OCO3)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc3c(c2)OCO3)CCC1
Yield: 66.4 %

Procedure:
1-(1-Benzo[1,3]dioxol-5-yl-cyclobutyl)-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (15 mg) was dissolved in 2 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (5 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 1-(1-benzo[1,3]dioxol-5-yl-cyclobutyl)-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanol (10 mg, 66%). Data for this mixture of diastereomeric amino alcohols: MS 478 (M+1); 1H NMR (300 MHz, CDCl3) partial: δ 6.7-7.8 (m, 7H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), the δ 3.1 singlet for the starting material was absent.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:4]([CH2:3][N:2]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN=Cc1ccccc1

Procedure:
To ethyl glycinate hydrochloride (36.4 g) suspended in 500 ml methylene chloride were added magnesium sulfate (22 g) and triethylamine (72 ml, 52.4 g). Benzaldehyde (27.6 g) was added dropwise at 15°-20° C. with stirring. The mixture was stirred at room temperature for two hours, filtered and stripped. To the residue was added 300 ml diethylether and 150 ml brine. After separation the organic layer was collected, and the aqueous layer was extracted with 100 ml ether. The organic phases were combined, dried (MgSO4), filtered and stripped to yield the title product as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:20]([CH2:23][CH3:24])[N:21]=[CH:22][C:3]=12.Cl.[NH2:26]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[CH2:23]([N:20]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:26][O:19][C:8]=3[C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=3)[C:3]=2[CH:22]=[N:21]1)[CH3:24]
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(C(F)(F)F)cc3)cnc21
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccc(C(F)(F)F)cc4)c3cnc21

Procedure:
4-Chloro-1-ethyl-5-(4-trifluoromethylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (3.10 g) was refluxed for 2 hours in 300 ml of acetic acid containing 9 g of hydroxylamine hydrochloride and 0.6 g of p-toluenesulfonic acid monohydrate. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed well with water, dried, evaporated, and purified by chromatography over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). In this way, 2.15 g of product was obtained, mp 243°-245°. Recrystallization from ethyl acetate gave analytically pure product, mp 244°-245° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][CH:13]([N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:14].C(N(C(C)C)C(C)C)C>ClCCl>[CH3:12][CH:13]([N:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:17][CH2:16]1)[CH3:14]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(C)N1CCCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCCN(C(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (209 mg, 1.21 mmol) in dichloromethane (4.00 ml) was added to a stirred solution of 1-propan-2-yl-1,4-diazepane (172 mg, 1.21 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.523 ml, 3.02 mmol) in dichloromethane (4.00 ml) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-propan-2-yl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (267 mg, 79%) as a cream oil which crystallised on standing. This was used directly with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.F[C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1)[O:12][C:14]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Product: N#Cc1cc(C=O)ccc1Oc1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-fluoro-5-(trifluoromethyl)phenol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9].[CH3:26][S:27](Cl)(=[O:29])=[O:28].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:4][CH:3]1[CH:8]([NH:10][C:11]1[N:16]=[C:15]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[CH:18]2)[CH:14]=[CH:13][N:12]=1)[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CNCCN1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(S(C)(=O)=O)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a 0° C. solution of 2-[1-(1-methylpiperazine-2-yl)-ethylamino]-4[-benzimidazol-1-yl]-pyrimidine (EXAMPLE 20; 6 mg) in 1 mL of CH2Cl2 and 0.5 mL of pyridine was added methanesulfonyl chloride (2.5 mg). The mixture was allowed to warm to room temperature and stirred overnight, then poured into 10 mL of 1M NaHSO4, extracted with 2×5 mL of CH2Cl2, basified (pH>10) with 5N NaOH, and extracted with 5×5 mL of EtOAc. The combined EtOAc extracts were washed with 5 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 9:1 CH2Cl2—2M NH3 in MeOH to provide 1.0 mg of the title compound. Mass spectrum (ESI) 416.3 (M+1).