Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: Cc1cc(C(=O)c2sc(N)nc2-c2ccco2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
Compound 331 (150 mg, 0.526 mmol) was dissolved in DMF (2 mL), and isonicotinic acid (259 mg, 2.10 mmol), EDC hydrochloride (403 mg, 2.10 mmol) and 1-hydroxybenzotriazole monohydrate (322 mg, 2.10 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 332 (78.0 mg, 38%).
Reaction SMILES: [C:1]([NH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][C:26]([OH:31])([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1.CO>C1COCC1>[C:1]([NH:20][CH:21]1[CH:22]2[CH2:23][CH:24]3[CH2:25][C:26]([O:31][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([C:33]5[O:32][C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=6[N:34]=5)=[CH:42][CH:43]=4)([CH2:27][CH:28]1[CH2:29]3)[CH2:30]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC12CC3CC(C1)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C3)C2
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C(NC2C3CC4CC2CC(OCc2ccc(-c5nc6ccccc6o5)cc2)(C4)C3)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To KH (35%; (0.34 g; 0.0029 mole) in THF (8 ml) under N2 and cooled in an ice bath is added N-trityl-5-hydroxytricyclo-[3.3.1.13,7 ]decan-2-amine (1.0 g; 0.0025 mole) This forms a pale yellow solution and is stirred at room temperature for 1 hour. The reaction mixture is then cooled in ice and 4-(benzoxazol-2-yl)benzyl bromide (0.7 g; 0.0025 mole) is added all at once. The mixture is stirred for 1/2 hour with ice cooling and then 31/2 hours at room temperature then cooled in ice and MeOH is added to quench the KH. The mixture is evaporated to dryness. Purification is accomplished on HPLC eluting with a gradient system staring with 10% and ending with 20% ethyl acetate/hexane to obtain N-trityl-5-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-2-amine which is used directly in step F.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]4[C:19]=3[C:14](=[CH:15][CH:16]=[CH:17]4)[N:13]=2)[CH:2]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>N1C=CC=CC=1>[N:13]1[C:14]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][C:20]=3[C:12]=1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: c1cncc(CCCCNC2=Nc3cccc4cccc2c34)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(c1cccc(C(F)(F)F)c1)N(CCCCc1cccnc1)C1=Nc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.0 grams of N-(4-(3-pyridinyl)butyl)benz(cd)indol-2-amine in 50 ml of pyridine was stirred as 2.5 ml of 3-trifluoromethylbenzoyl chloride was slowly added. The reaction mixture was stirred at room temperature for 18 hours, and drowned onto 500 ml of ice. The precipitate was collected, washed with water and dried. Recrystallization from chloroform-hexane gave 3.95 grams of the title product, mp 122° C.-123° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:4](I)[CH:3]=1.[F:18][C:19]([F:30])([F:29])[CH2:20][S:21][CH2:22][C:23]([OH:28])([CH2:26][CH3:27])[C:24]#[CH:25]>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9])[N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[C:24]([C:23]([OH:28])([CH2:26][CH3:27])[CH2:22][S:21][CH2:20][C:19]([F:30])([F:18])[F:29])=[CH:25]2
Reactant: C#CC(O)(CC)CSCC(F)(F)F
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(F)cc1I
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc(F)c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as describe in General Procedures Example C, reacting N-(4-fluoro-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (0.57 g, 1.5 mmol) and 3-(2,2,2-trifluoro-ethylsulfanylmethyl)-pent-1yn-3-ol (0.32 g, 1.5 mmol) to yield the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:18][OH:19])[CH2:9][NH:10]C(=O)OC(C)(C)C.ClS([N:24]=[C:25]=[O:26])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:25](=[O:26])([O:19][CH2:18][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:9][NH2:10])[NH2:24]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(CO)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCC(COC(N)=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 344 mg (1.20 mmol) of the compound of Example 14A in 86 ml of acetonitrile was cooled to −15° C., and 314 μl (3.61 mmol) of chlorosulphonyl isocyanate were added. After 5 min, 10 ml of water were added and stirring of the reaction mixture was continued at 60° C. overnight. After cooling to RT, 10 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (118 mg, about 85% pure, about 37% of theory) corresponded to the title compound and was reacted further without further purification.
Reaction SMILES: [NH4+].[Cl-].[CH2:3]([N:10]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:11]([C:15]1([O:21][C:22]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[C:24]([F:31])[C:23]=2[F:32])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:12]([OH:14])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.[Zn]>[NH2:28][C:27]1[C:22]([O:21][C:15]2([CH:11]([N:10]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:12]([OH:14])=[O:13])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[C:23]([F:32])[C:24]([F:31])=[CH:25][CH:26]=1
Reactant: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(Oc2c([N+](=O)[O-])ccc(F)c2F)CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(F)c(F)c1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCOCC1
Temperature: 65 °C
Yield: 85.4 %

Procedure:
NH4Cl (48.0 mg, 0.90 mmol, Eq: 2) and Zn powder (440 mg, 6.73 mmol, Eq: 15) were added to a solution of 2-(dibenzylamino)-2-(4-(2,3-difluoro-6-nitrophenoxy)tetrahydro-2H-pyran-4-yl)-acetic acid (230 mg, 449 μmol, Eq: 1.00) in MeOH (10 mL) and the mixture was heated to 65° C. After 2 h the mixture was filtered through Celite. The filtrate was concentrated and partitioned between 1 N NaOAc and EtOAc. The organic layer was dried over Na2SO4 then concentrated under reduced pressure to afford [4-(6-amino-2,3-difluoro-phenoxy)-tetrahydro-pyran-4-yl]-dibenzylamino-acetic acid (185 mg) which was used without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]1[NH:13][C:14]2[C:19]([C:20]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[H][H]>[Pd].CO.O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: C(=C/c1[nH]c2ccccc2c1Sc1ccccc1)\c1nc2ccccc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(Sc2c(CCc3nc4ccccc4o3)[nH]c3ccccc23)cc1

Procedure:
A solution of trans-2-(2-benzoxazol-2-ylethenyl)-3-phenylthioindole (0.420 g, 1.14 mmol) in 1:1 methanol/tetrahydrofuran (250 mL) was stirred under 1 atmosphere of hydrogen in the presence of 10% palladium on charcoal (100 mg). Additional catalyst was added as needed to drive the reaction to completion. The catalyst was removed by filtration, and the filtrate concentrated in vacuo. The resulting solid was triturated with 10% ethyl acetate in hexane and collected by filtration to afford the title compound, mp 192°-193° C. Anal. calc. for C23H18N2OS: C, 72.80; H, 5.04; N, 7.38. Found: C, 72.78; H, 4.95; N, 7.45.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cn1ccnc1C(=NOCc1nccc(N)n1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccnc1C(=NOCc1nccc(NC(=O)C2CC2)n1)c1ccccc1
Yield: 7 %

Procedure:
A solution of 2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.64 mmol), triethylamine (0.18 mL, 1.29 mmol), cyclopropanecarboxylic acid chloride (136 mg, 1.29 mmol) in dichloromethane (10 mL) was stirred 6 h30 at room temperature. After dilution with water (50 mL), the layers were separated and the aqueous layer further extracted with dichloromethane (30 mL). The combined organic layers were dried over MgSO4 and the solvents removed in vacuo. Purification on silica gel afforded N-{2-[({[(1-methyl-1 H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}cyclopropanecarboxamide as an oil [19 mg, yield 7%; HPLC/MS: m/z=377 (M+H); log P(HCOOH)=1.50].
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:32])[N:4]([C:21]2[CH:26]=[C:25]([C:27](=O)[C:28]#[CH:29])[CH:24]=[CH:23][C:22]=2[CH3:31])[C:5]([CH3:20])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=1.Cl.[OH:34][C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[NH:37].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:32])[N:4]([C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][N:38]=[C:36]([C:35]([OH:34])([CH3:40])[CH3:39])[N:37]=3)[CH:24]=[CH:23][C:22]=2[CH3:31])[C:5]([CH3:20])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C(F)(F)F)n3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2cccc(C(F)(F)F)n2)c(Cl)c1=O
Temperature: 75 °C
Yield: 31.6 %

Procedure:
To a solution of 5-chloro-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-6-(6-trifluoromethyl-pyridin-2-ylmethoxy)-3H-pyrimidin-4-one of Step C (50 mg, 0.11 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (23 mg, 0.16 mmol) and potassium carbonate (45 mg, 0.33 mmol) and the slurry heated at 75° C. for eighteen hours. After cooling to room temperature the reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a yellow oil (19 mg, 32% yield). MS (M+H): 546; 1H NMR (400 MHz, chloroform-d) δ ppm, 1.64 (s, 6H), 2.15 (s, 3H), 2.21 (s, 3H), 5.69-5.78 (m, 2H), 7.56-7.59 (m, 2H), 7.66 (d, J=7.43 Hz, 1H), 7.82 (d, J=7.82 Hz, 1H), 7.94-8.00 (m, 2H), 8.14 (d, J=7.43 Hz, 1H), 8.78 (d, J=5.08 Hz, 1H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[P:28](=[O:32])([OH:31])([OH:30])[OH:29]>O>[P:28]([OH:32])([OH:31])([OH:30])=[O:29].[S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cc2ccsc2cn1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: O
Product: OB(O)c1cc2ccncc2s1
Temperature: -44 °C
Reaction time: 1.25 h
Yield: 113.3 %

Procedure:
A three neck flask fitted with an internal thermometer containing the material from Step iii (4.12 g, 30.5 mmol) was evacuated and then filled with nitrogen atmosphere, THF (50 mL) was added and the solution cooled to −44° C. (CH3CN/dry ice). n-Butyllithium (1.6M/hexane, 21 mL, 34 mmol) was added over 10 minutes, while maintaining the internal temperature at or below −35° C. The reaction was stirred at −33 to −45° C. for 75 minutes. Triisopropyl borate (8.4 mL, 36.6 mmol) was added and the cooling bath removed. The reaction was stirred for one hour then phosphoric acid (85% aqueous, 2.5 mL, 33.5 mmol) was added. The reaction was diluted with 10 mL water resulting in a precipitate. The reaction was stirred vigorously for 15 minutes. A yellow solid was collected by filtration, rinsing with EtOAc (about 50 mL) to provide a white powdery solid (9.57 g). Approximately half of the material was washed with 50 mL water to isolate 3.16 g of a pale pink solid. Both crops of material are the same as determined by spectral data. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.87 (1H, d, J=5.5 Hz), 7.95 (1H, s), 8.41 (1H, d, J=5.7 Hz), 9.11 (1H, s).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])N.N([O-])=[O:19].[Na+]>O>[Cl:6][C:7]1[CH:8]=[C:9]([OH:19])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]
Reactant: O=N[O-]
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a sulfuric acid (14 ml) —H2O (14 ml) solution of 3-chloro-4-(trifluoromethyl)aniline (1.96 g, 10 mmol) was added a H2O (10 mL) solution of sodium nitrite (828 mg,12 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was poured into 10 M sulfuric acid (50 mL). The stirred mixture was refluxed at 110 ° C. for 2 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a ethyl acetate/hexane=⅓ to furnish 945 mg (48% yield) of the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:8]=2)=[CH:4][CH:3]=1.Br.C([O-])([O-])=O.[K+].[K+].[CH3:34][O:35][CH2:36][CH2:37]Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH:36]([O:35][CH3:34])[CH3:37])[CH2:20][CH2:19]3)[N:8]=2)=[CH:25][CH:26]=1
Reactant: O=c1c2ccccc2c(Cc2ccc(Cl)cc2)nn1C1CCCNCC1
Reactant: COCCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COC(C)N1CCCC(n2nc(Cc3ccc(Cl)cc3)c3ccccc3c2=O)CC1
Temperature: 25 °C

Procedure:
6 grams (0.013 mole) of 4-(4-chlorobenzyl)-2-(hexahydroazepin-4-yl)-1-(2H)-phthalazinone× HBr were stirred together with 3.6 grams (0.026 mole) of K2CO3, 7.4 grams (0.078 mole=7.1 ml) of 2-chloroethyl methyl ether and 30 ml of dimethylacetamide for 21/2 hours at an oil bath temperature of 120° C. Subsequently the mixture was cooled to room temperature and filtered off with suction from the insolubles. The solution was concentrated in a vacuum and the brownish oil obtained chromatographed by means of a silica gel column (elution agent: CH2Cl2 /CH3OH=90:10). The desired fractions were combined and the solvent distilled off on the rotary evaporator. The oily residue was made acid with isopropanol/HCl. The hydrochloride was precipitated as a viscous mass by addition of ether. After decanting off the supernatant solution the residue was triburated with methyl ethyl ketone at boiling heat, whereby the desired hydrochloride was obtained as a crystalline product. M.P. 194°-197° C. Yield: 1.8 grams (28%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[C:11](=[O:12])[NH:10][C:9](=[O:13])[O:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=2)=[C:19]([CH3:31])[CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+:49]>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:1][C:2]3[CH:15]=[CH:14][C:5]([CH2:6][N:7]4[C:11](=[O:12])[N-:10][C:9](=[O:13])[O:8]4)=[CH:4][CH:3]=3)[CH:24]=2)=[C:19]([CH3:31])[CH:18]=1.[Na+:49]
Reactant: Nc1ccc(Cn2oc(=O)[nH]c2=O)cc1
Reactant: Cc1cc(Cl)ccc1-c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-c1cccc(CNc2ccc(Cn3oc(=O)[n-]c3=O)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.9 %

Procedure:
A mixture of 2-(4-aminobenzyl)-1,2,4-oxadiazolidine-3,5-dione (500 mg), 4′-chloro-2′-methylbiphenyl-3-carbaldehyde (668 mg), acetic acid (0.33 ml) and THF (40 ml) was stirred at room temperature for 24 hours. Sodium triacetoxyborohydride (767 mg) was added to the reaction mixture, followed by stirring at room temperature for 15 minutes. The solvent was evaporated under a reduced pressure, and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution, the solvent was evaporated under a reduced pressure, toluene was added to the residue, and the solvent was again evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and THF (5 ml), methanol (5 ml) and a 1 M sodium hydroxide aqueous solution (1.47 ml) were added to the resulting pale yellow foamy substance (620 mg), followed by stirring at room temperature for 5 minutes. The solvent was evaporated under a reduced pressure, the residue was purified by an ODS column chromatography (water-acetonitrile) and made into a solid by adding diethyl ether. The solid was collected by filtration and then dried by heating under a reduced pressure to obtain sodium 2-(4-{[(4′-chloro-2′-methylbiphenyl-3-yl)methyl]amino}benzyl)3,5-dioxo-1,2,4-oxadiazolidin-4-ide (160 mg) as a white solid.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[O:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccncc2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-4-boronic acid. The title compound (701 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23](O)=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(Cl)(=O)C([Cl:31])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23]([Cl:31])=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)O)O2
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)Cl)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
201.0 g (0.57 mole) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid was dissolved in 1.0 L toluene and transferred to a 3 L three necked flask equipped with a Dean-Stark trap and condenser, magnetic stirrer and a thermometer connected to a heating mantle. The solution was refluxed 1 hour with no appreciable amount of water collecting in the Dean-Stark trap. This was removed, and the solution was cooled to 50° C. Then a pressure equalizing addition funnel was placed on top and the oxalyl chloride 58.5 mL (0.68 mole, 1.2 equiv.) was added dropwise at about one drop per second. The color became orange, and the temperature increased to about 60° C. as gas evolution began smoothly. The rate of addition was monitored so that gas evolution was not too vigorous. The gas evolved was bubbled through two aqueous sodium hydroxide traps. The slow addition was continued over about 1 hour and then heating was applied with a thermowatch keeping the heat at 60° C. The solution was then condensed on the rotovap, and after pumping off any residual solvent for 2 hours, 215.2 g (>100%) of (S)-(6-benzyloxy-2,5,7,8-tetramethyl chroman-2-yl)acetic acid chloride was obtained (211.45 g theoretical).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[C:5]=12.[H-].[Na+].Cl[C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH:6]([C:10]3[CH:11]=[CH:12][C:13]([O:16][C:20]4[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:23]5[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=5[N:21]=4)=[CH:14][CH:15]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(C2CCCn3ccnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(C3CCCn4ccnc43)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.6 %

Procedure:
To a solution of 4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-yl)phenol (0.13 g) in DMF (10 ml) was added sodium hydride (60% in oil, 0.024 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.17 g) obtained in Example 1, step A), and the mixture was stirred under microwave irradiation at 150° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.19 g).