Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24].Cl.[OH-].[Na+]>O.C(O)C>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(O)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 26.9 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and neutralized with aqueous 2N NaOH to pH 6–7. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow solid (18 mg, 27%). 1H NMR (Acetone-d6): 9.53–9.51 (m, 1H), 8.85 (s, 1H), 8.71 (dd, J=1.8, 4.8 Hz, 1H), 8.67–8.63 (m, 1H), 8.49 (s, 1H), 7.53–7.48 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.98 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([N+:15]([O-])=O)=[CH:8][C:7]=1[O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH3:2].O.NN>[Pd].C(O)C>[CH2:25]([CH:20]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:19][O:18][C:7]1[CH:8]=[C:9]([NH2:15])[C:10]([NH2:12])=[CH:11][C:6]=1[O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:27][CH2:28][CH2:29][CH3:30])[CH3:26]
Reactant: CCCCC(CC)COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OCC(CC)CCCC
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCC(CC)COc1cc(N)c(N)cc1OCC(CC)CCCC

Procedure:
A 250 mL 3-neck round bottom flask fitted with a condenser is charged with 1,2-bis((2-ethylhexyl)oxy)-4,5-dinitrobenzene (8.9 g, 0.021 mol), hydrazine monohydrate (11.6 g, 0.231 mol), Pd/C (0.27 g), and ethanol (100 mL). The mixture is warmed to reflux under nitrogen overnight. The mixture is filtered while hot under a nitrogen blanket. A solid is precipitated out upon cooling, washed with methanol and dried overnight under vacuum to yield the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:23][CH3:24])[C:11](=[O:25])[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCN1C(=O)CN=C(c2ccc(Br)cc2)c2cc(OC)c(OC)cc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCN1C(=O)CN=C(c2ccc(-c3ccccc3)cc2)c2cc(OC)c(OC)cc21
Temperature: 90 °C
Yield: 57.3 %

Procedure:
Heat at 90° C. for 12 hours under an inert atmosphere a mixture of 100 mg (0.27 mmol) of 5-(4-bromophenyl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbl), 35 mg (0.30 mmol) of benzene boronic acid, 215 μl of 2M Na2CO3, 25 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) and 250 μl of EtOH in 5 ml of degassed toluene. Allow to cool to room temperature. Evaporate to dryness. Purify by chromatography (AcOEt). Recrystallize in Et2O. One obtains 62 mg of the abovenamed product in the form of colorless crystals. Yield: 52%. M: 149–150° C. 1H-NMR (CDCl3, 200 MHz): d 1.13 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.95 (AB system, ? d=0.57, JAB=13.7, 2H, —NCH2), 3.98 (s, 3H, OCH3), 4.29 (AB system, ? d=0.99 JAB=10.0, 2H, CH2), 6.75 (s, 1H Ar), 6.86 (s, 1H Ar), 7.37–7.75 (m, 9H Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:18][C:19]3[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:32][CH:33]=O.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([S:18][C:19]4[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=4)=[CH:7][CH:8]=3)[N:3]3[CH:32]=[CH:33][N:1]=[C:2]3[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=CCCl
Reactant: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(N)nc3c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nccn4c3c2)c1
Temperature: 80 °C

Procedure:
To 10q (200 mg, 0.48 mmol) in 1,4-dioxane (4 mL) was added chloroacetaldehyde (0.07 mL, 0.53 mmol), sodium bicarbonate (243 mg, 2.89 mmol), and water (2 mL). The mixture was heated to 80° C. for 5 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10r.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.CN(C)C([N:14]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][O:22][Si](C)(C)C)[N:16]=[CH:15]1)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:16]2[C:17]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:18][N:14]=[CH:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)c1
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Solvent: CC#N
Product: OCCCc1cncn1Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 250 parts of 1-bromo-3-bromomethylbenzene, 168.5 parts of N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide and 869 parts of acetonitrile was refluxed for 18 hours. After cooling to 0° C., ammonia was bubbled through the reaction mixture for 5 min. The solvent was evaporated and the residue was stirred for 1 hour in 1700 ml of hydrochloric acid 1N. The mixture was extracted with ethyl acetate. The aqueous layer was basified with Na2CO3 (sat.) and reextracted with ethyl acetate (5×450 parts). The combined extracts were washed with water, dried, filtered and evaporated, yielding 210 parts (100%) of 1-[(3-bromophenyl)methyl]-1H-imidazole-5-propanol (interm. 1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]4)=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]2[C:30]([O:32][C:33](=O)[C:23]=2[CH:22]=1)=[O:31]>>[O:9]1[C:10]2[CH:20]=[C:19]3[C:14](=[CH:13][C:11]=2[N:12]=[C:8]1[C:4]1[CH:3]=[C:2]([N:1]2[C:30](=[O:31])[C:24]4[C:23](=[CH:22][CH:21]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=4)[C:33]2=[O:32])[CH:7]=[CH:6][CH:5]=1)[CH:15]=[CH:16][CH:17]=[CH:18]3
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: Nc1cccc(-c2nc3cc4ccccc4cc3o2)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4cc5ccccc5cc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)naphth[2,3-d]oxazole (36 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the title compound was obtained, 30 mg (44%). 1H NMR (DMSO) δ 8.45(m, 2H), 8.38(d, 3H), 8.30(s, 1H), 8.12(m, 3H), 7.82(m, 2H), 7.55(m, 2H). MS 433 m/z (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>CN(C)C=O>[N+:28]([C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:26])[F:27])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])([O-:30])=[O:29]
Reactant: O=C(O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])c1
Yield: 73.5 %

Procedure:
3-Hydroxybenzoic acid (13.8 g) in dry dimethylformamide (100 ml) was heated and stirred for 7 hours at 100° with anhydrous potassium carbonate (26 g) and 4-chloro-3-nitrobenzotrifluoride (22.5 g). The mixture was then evaporated to a small volume under reduced pressure and diluted with water. With warming, a dark solution was obtained. Acidification gave a white precipitate; this was washed with water and recrystallised from a mixture of methanol and water to give 3(2-nitro-4-trifluoromethylphenoxy)benzoic acid (24 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>C(O)(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13](=[O:15])[CH3:14])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1
Reactant: Nc1ccc(O)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1C(F)(F)F
Temperature: 25 °C

Procedure:
4-Amino-3-trifluoromethylphenol (0.212 g; 1.2 mmol) was dissolved in 10 ml of glacial acetic acid under nitrogen atmosphere and acetic anhydride (0.3 ml; 3.0 mmol) was added followed with stirring for an hour at room temperature. Water (0.5 ml) was added into the reaction mixture and then evaporated to dryness. Toluene (50 ml) was added and the evaporation was repeated to give a quantitative yield of pure N-(4-Hydroxy-2-trifluoromethylphenyl)acetamide. 1H NMR (400 MHz, DMSO-d6): 1.99 (3H, s), 7.01 (1H, dd, J=8.6 Hz, J=2.6 Hz), 7.02 (1H, d, J=2.5 Hz), 7.19 (1H, d, J=8.4 Hz), 9.33 (1H, s), 10.08 (1H, br s).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[S:12][CH2:11][CH2:10][N:5]2[C:6](=[O:9])[C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][O:1][C:2]3[N:3]=[C:4]4[S:12][CH2:11][CH2:10][N:5]4[C:6](=[O:9])[C:7]=3[CH3:8])=[CH:28][CH:27]=2)=[O:25])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1c(O)nc2n(c1=O)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2n(c1=O)CCS2
Temperature: 60 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
To a solution of 7-hydroxy-6-methyl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-one (1.0 g) and potassium carbonate (750 mg) in DMF (15 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (2.0 g) and the mixture was stirred at 60° C. for 2 hours. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane-ethyl acetate =1:1) and recrystallized from isopropyl ether to provide the title compound as colorless solid (200 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][OH:22])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl.CC(=O)OCC>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[C:23]([CH3:25])[C:18]([O:19][CH2:20][CH2:21][O:22][S:41]([CH3:40])(=[O:43])=[O:42])=[C:17]([CH2:26][CH3:27])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:28])[N:5]=1)[CH3:30]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
To a solution of 2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethanol (850 mg, 2.07 mmol) and DIPEA (401 mg, 3.11 mmol) in DCM (20 mL), methane sulfonylchloride (285 mg, 2.49 mmol) is slowly added. The mixture is stirred at rt for 30 min before it is diluted with EA and washed with sat. aq. NaHCO3-solution. The washing is extracted back three times with EA. The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give crude methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester (925 mg) as a yellow solid; LC-MS: tR=0.94 min; [M+1]+=489.18.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20](=O)[CH3:21]>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH:20]([NH:4][CH2:3][CH:2]([OH:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:21]
Reactant: CC(=O)Cc1ccc(C)cc1C
Reactant: NCC(O)c1ccccc1
Product: Cc1ccc(CC(C)NCC(O)c2ccccc2)c(C)c1

Procedure:
The title compound was reprepared as a 49:51 mixture of diastereoisomers m.p. 58-63 in the manner described in Example 3 using 2-hydroxy-2-phenylethanamine and (2,4-dimethylphenyl)propanone. 'Hnmr identical with that of Example 32.
Reaction SMILES: [Na].Cl.[F:3][C@@H:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1.C([O:26][C:27](=O)[CH:28]([CH2:34][CH2:35][C@@H:36]([F:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:29](OCC)=[O:30])C.Cl>CO>[OH:26][C:27]1[C:28]([CH2:34][CH2:35][C@@H:36]([F:43])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:29]([OH:30])[N:13]=[C:11]([C:10]2[CH:14]=[CH:15][C:7]([O:6][CH2:5][C@@H:4]([F:3])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=2)[N:12]=1
Reactant: CCCCCC[C@H](F)CCC(C(=O)OCC)C(=O)OCC
Reactant: CCCCCCCC[C@H](F)COc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCCCCCC[C@H](F)COc1ccc(-c2nc(O)c(CC[C@@H](F)CCCCCC)c(O)n2)cc1
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
Under nitrogen atmosphere, 2.4 ml of dry methanol was placed in a two-necked round-bottomed flask. To the methanol, 90 mg (3.93 mM) of metal sodium was added and dissolved therein. To the solution, 519 mg (1.57 mM) of (S)-4-(2-fluorodecyloxy)benzamidine hydrochloride was added and stirred for 20 minutes. To the mixture, a solution of 400 mg (1.31 mM) of (S)-2-(3-fluorononyl)malonic diethyl ester in 1 ml of dry methanol was added, followed by stirring for 16 hours at room temperature and distilling-off of methanol under reduced pressure. To the resultant reaction mixture, 4 ml of 6M-HCl was added to precipitate a crystal. The crystal was recovered by filtration and washed with ethanol and Et2O and further dried under reduced pressure. The resultant crystal was recrystallized from DMF to obtain 390 mg (0.77 mM) of 4,6-dihydroxy-5-((3S)-3-fluorononyl)-2-[4-((2S)-2-fluorodecyloxy)phenyl]pyrimidine (Yield: 58.8%).
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][CH:7]([CH2:9][CH3:10])[CH:6]([CH3:11])[CH:5]=N1)[CH3:2].[Cl-].[NH4+]>>[CH2:9]([C:7]1[C:6]([CH3:11])=[CH:5][C:1]([CH3:2])=[CH:3][N:8]=1)[CH3:10]
Reactant: CCC1N=CC(C)C(CC)N1
Agent: [Cl-]
Agent: [NH4+]
Product: CCc1ncc(C)cc1C

Procedure:
A sample of 204.6g. of 2,4-diethyl-5-methyl-2,3,4,5-tetrahydropyrimidine and 0.8g. of ammonium chloride were heated over a 3/4 hr. period to reflux and refluxed for 5 hrs. Distillation yielded 125.1g of 2-ethyl-3,5-dimethylpyridine. b760 195°-205°C.; nuclear magnetic resonance spectrum, no solvent, δ in ppm, 8.17, m, 1H; 7.03 m, 1H; 2.08 s, 6H; 2.68 q, 2H; 1.23 t, 3H.
Reaction SMILES: [NH3:1].[C:2]1([C:8](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][Cl:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1>[ClH:10].[C:2]1([C:8](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][NH2:1])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: ClCC(=Cc1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cl
Product: NCC(=Cc1ccccc1)c1ccccc1

Procedure:
Ammonia under pressure is added to a solution of 4 parts of 2,3-diphenylallyl chloride in 44 parts of benzene at 70° for 24 hours. After that time, the solid is separated by filtration and the benzene solution is reduced to an oil under reduced pressure. The oil is dissolved in isopropanolic hydrochloric acid and then diluted with ethyl ether to precipitate a solid. The solid is collected by filtration and dried to yield pure 2,3-diphenylallylamine hydrochloride, displaying nuclear magnetic resonance maxima at about 240, 241, 413, 426 and 442 Hertz and represented by the following structural formula ##STR5##
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][C:15]#N)=[CH:13][C:8]=3[N:7]([CH3:17])[C:6]2=[O:18])[CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:20].[OH2:24]>>[CH:1]1([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][C:15]([OH:20])=[O:24])=[CH:13][C:8]=3[N:7]([CH3:17])[C:6]2=[O:18])[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(=O)n(C2CCC2)c2ccc(CC#N)cc21
Reactant: O
Reactant: O=S(=O)(O)O
Product: Cn1c(=O)n(C2CCC2)c2ccc(CC(=O)O)cc21
Temperature: 110 °C

Procedure:
(1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-acetonitrile (11.5 g) was diluted with sulfuric acid:water (1:1, 25 mL) and was heated to 110° C. for 4 hour then cooled and extracted into ethyl acetate, dried over sodium sulfate and concentrated to give 11.99 g of (1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH2:7][C:8]2[N:17]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:16](=[O:27])[C:15]3[C:10](=[C:11]([O:28][CH3:29])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:17]([CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:23][CH2:22]3)[C:16](=[O:27])[C:15]3[C:10](=[C:11]([O:28][CH3:29])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:30][CH:31]=1
Reactant: ClCCCN1CCCCC1
Reactant: COc1cccc2c(=O)n(CCCC3CCNCC3)c(COc3ccc(Cl)cc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)n(CCCC3CCN(CCCN4CCCCC4)CC3)c(COc3ccc(Cl)cc3)nc12
Temperature: 25 °C

Procedure:
A solution of 2-(4-chloro-phenoxymethyl)-8-methoxy-3-(3-piperidin-4-yl-propyl)-3H-quinazolin-4-one (150 mg, 0.31 mmol), N-(3-chloropropyl)-piperidine hydrochloride (222 mg, 0.63 mmol), K2CO3 (87 mg, 0.63 mmol), Kl (105 mg, 0.63 mmol) was heated at 80° C. in THF/H2O (3:1 mixture, 30 mL) for 17 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc. The organic solution was separated and was washed with sat'd aq NaHCO3, sat'd aq NaCl, dried and concentrated. The crude residue was chromatographed on SiO2-gel using EtOAc/NEt3 (10:1) to give the desired product as an oil. API-MS: 567.2 (M+1). 1H NMR (300 MHz, d4-MeOH): d 7.75 (d, 1 H), 7.5 (t,1 H), 7.38 (d, 1 H), 7.3 (d, 2 H), 7.1 (d, 2 H), 5.25 (s, 2 H), 4.1 (m, 2 H), 4.0 (s, 3 H), 2.9 (m), 2.4-2.1 (m), 1.9-1.1 (m).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14](OC)=[O:15])[CH2:4][O:3]1.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1>[CH:14]([C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a −78° C. solution of (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (Intermediate 181, 18.80 g, 72.50 mmol) in toluene (153 mL) was dropwise (via addition funnel) added DIBAL-H (1.0 M in toluene) (116 ml, 116.01 mmol) over 1.5 hours. The reaction mixture was stirred at −78° C. for 2 hours under nitrogen atmosphere. The cold reaction mixture was treated with 38 mL MeOH (˜1.91 M) and then poured 750 mL cold 1N HCl (˜0.09M) into reaction mixture, removed reaction mixture from −78° C. bath, transferred to separatory funnel and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, concentrated. Due to a difficult separation required two silica gel chromatography columns (0%-50% ethyl acetate/hexanes) to afford the title compound as a colorless oily solid (10.2 g, 61%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7](Cl)=[O:8].[C:11]([CH:13]([OH:27])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([O:27][CH:13]([C:11]#[CH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:8]
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(OC(=O)C1C(C)(C)C1(C)C)c1cccc(Oc2ccccc2)c1
Reaction time: 16 h

Procedure:
2,2,3,3-Tetramethylcyclopropanoyl chloride (3.05 g) was added with stirring to a solution of α-ethynyl-3-phenoxybenzylalcohol (4.8 g) and triethylamine (2.16 g) in dry toluene (70 ml) at 10° C. The solution was allowed to attain room temperature and stirred for 16 hours. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was washed with 5% sulphuric acid, followed by saturated sodium bicarbonate solution and finally purified by chromatography on silica gel using toluene as eluent to give the desired product as an oil nD20 1.5455.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH3:28])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH2:29]([N:31]([CH2:34]C)[CH2:32]C)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:38]>CN(C)C=O.CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH3:28])=[C:16]([CH:23]4[CH2:24][N:25]([C:29]([N:31]([CH3:34])[CH3:32])=[O:38])[CH2:26]4)[C:17]([C:18]#[N:19])=[C:20]([Cl:22])[CH:21]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile (chiral intermediate from Example 261) (40 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL) was treated with triethylamine (40 μL, 0.29 mmol) followed by p-nitrophenyl chloroformate (23 pt, 0.13 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product that was used immediately. A solution of the p-nitrophenyl carbamate intermediate in tetrahydrofuran (1 mL) was treated with triethylamine (15 μL, 0.11 mmol) followed by a solution of 1.0 M dimethylamine in tetrahydrofuran (150 μL, 0.15 mmol) and heated in a sealed tube at 60° C. for 2 h. The reaction mixture was concentrated, diluted with methanol and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (13 mg, 28%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.49 (s, 1H), 7.36 (br s, 2H), 6.25 (q, J=7.0 Hz, 1H), 4.44-4.23 (m, 3H), 4.22-4.10 (m, 2H), 3.69 (s, 3H), 2.76 (s, 6H), 2.55 (s, 3H), 1.73 (d, J=7.1 Hz, 3H). LCMS for C22H26ClN8O2 (M+H)+: m/z=469.2; Found: 469.1.