Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]1([C:17]2([CH:27]=O)[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:29][C:30]([F:56])([F:55])[C:31]1[CH:32]=[C:33]([CH2:41][CH2:42]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.[Cl-].[NH4+]>O1CCCC1.O>[C:11]1([C:17]2(/[CH:27]=[CH:42]/[CH2:41][C:33]3[CH:34]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:36]=[C:31]([C:30]([F:29])([F:55])[F:56])[CH:32]=3)[CH2:18][CH2:19][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:25][CH2:26]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC1(c2ccccc2)CCC2(CC1)OCCO2
Reactant: O=S(=O)(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nc2ccccc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(C/C=C/C2(c3ccccc3)CCC3(CC2)OCCO3)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Lithium hexamethyldisilazide (1M in tetrahydrofuran, 7.0 mL, 7.0 mmol) was added over 10 minutes to a cooled (−78° C.) solution of 8-phenyl-1,4-dioxaspiro[4,5]decane-8-carboxaldehyde (J. Med. Chem. 1975, 18, 593-599, 1.68 g, 6.8 mmol) and 2-({(2-[3,5-bis(trifluoromethyl)phenyl]ethyl}sulfonyl)benzothiazole (Description 34, 2.99 g, 6.8 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred at −78° C. for 1 hour, then allowed to warm to room temperature. Aqueous ammonium chloride (saturated, 10 mL) was added and the mixture was stirred at room temperature for 30 minutes. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10) to give the tide compound as a pale yellow oil (2.43 g, 92%).
Reaction SMILES: [NH:1]([C:5]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C(C)=O.[OH-].[Na+].C([OH:23])C>O>[NH2:1][C:5]1[CH:16]=[CH:15][C:14]([C:17](=[O:23])[NH2:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CCO
Reactant: CCN(CC)Cc1cc(C#N)ccc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)Cc1cc(C(N)=O)ccc1N
Reaction time: 4 h

Procedure:
A mixture of 10 gm of 2-acetamino-5-cyano-N,N-diethyl-benzylamine, 100 ml of 5 N sodium hydroxide and 70 ml of ethanol was boiled for 4 hours. Thereafter, the reaction solution was cooled, diluted with 200 ml of water and extracted three times with 250 ml of chloroform each. The combined chloroform extracts were dried over sodium sulfate and evaporated in vacuo, and the residue was recrystallized from ethanol. The 2-amino-5-carbamoyl-N,N-diethyl-benzylamine of m.p. 129-131° C was obtained.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH2:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:24]1([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[CH:28]=[N:27][N:26]=[N:25]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=N>CN(C)C=O.O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:15][C:10]=3[N:9]=[C:8]2[NH:23][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[C:29]([N:24]3[CH:28]=[N:27][N:26]=[N:25]3)[CH:30]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc(-n2cnnn2)c1
Reactant: Nc1nc2cc(CN3CCCCC3)ccc2n1C1CCCCC1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(CN3CCCCC3)ccc2n1C1CCCCC1)c1cccc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-cyclohexyl-5-piperidin-1-ylmethyl-1H-benzimidazol-2-amine (100 mg, 0.32 mmol, prepared above) and 3-(1-tetrazolyl)-benzoic acid (76 mg, 0.40 mmol) in N,N-dimethylformamide (2 mL) was added 1-hydroxybenzotriazole (57 mg, 0.42 mmol) followed by 1-(3-dimethylaminopropyl)carbodiimide hydrochloride (80 mg, 0.42 mmol). N,N-diisoproplethylamine (100 mg, 0.77 mmol) was then added and the solution was allowed to stir at room temperature. After 18 hr, the reaction mixture was diluted with N,N-dimethylformamide (2 mL) and water (1 mL), filtered, and purified without work-up by preparative scale HPLC. Freeze-drying afforded (N-(1-cyclohexyl-5-piperidin-1-ylmethyl-1H-benzimidazol-2-yl)-3-(1-tetrazolyl) benzamide) as a cream solid (27 mg, 0.056 mmol): 1H NMR (DMSO-d6, 300 MHz) δ 10.20 (s, 1H), 9.30 (broad s, 1H), 8.63 (s, 1H), 8.34 (d, J=10.0 Hz, 1H), 8.02 (d, J=10 Hz, 1H), 7.81-7.64 (m, 2H), 7.64 (s, 1H), 7.33 (d, J=10.0 Hz, 1H), 4.83-4.63 (m, 1H), 4.41-4.29 (m, 2H), 2.99-1.33 (m, 18H). MS: API m/z 485 (M+H+)
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CO>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.42 mL, 2.1 mmol) and benzyl bromide (162 μL, 1.4 mmol), and the mixture was stirred at 40° C. for 3 hr. Then, water (2 mL) was added to make the system homogeneous, which system was analyzed by HPLC. As a result, the objective N-Boc-(O-benzyl)tyrosine (353 mg, conversion yield 95%) was confirmed.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]=[CH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[NH:23]C(OC(C)(C)C)=O)[C:10](=[O:31])[CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[S:37][C:36]([CH:38]=[CH:39][S:40](Cl)(=[O:42])=[O:41])=[CH:35][CH:34]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC#N>[NH2:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH2:16][CH:15]=[CH:14][N:11]1[CH2:12][CH2:13][N:8]([S:40]([CH:39]=[CH:38][C:36]2[S:37][C:33]([Cl:32])=[CH:34][CH:35]=2)(=[O:42])=[O:41])[CH2:9][C:10]1=[O:31]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1CC=CN1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1ccncc1CC=CN1CCN(S(=O)(=O)C=Cc2ccc(Cl)s2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[3-(4-tert-Butoxycarbonylamino-pyridin-3-yl)-propenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester from EXAMPLE 96, Part B (45 mg, 0.10 mmol) is dissolved in 20% TFA/CH2Cl2 and stirred at r.t. for 2 hours. The solution is concentrated to residue. The residue is dissolved in MeCN (2.5 ml) and treated with 4-methylmorphorline (0.027 ml, 0.25 mmol). 2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl chloride (24 mg, 0.10 mmol), EXAMPLE 3, in MeCN (1 mL) is then added dropwise. The reaction mixture is stirred at r.t. for 1 h, then subjected to reverse phase HPLC purification, to give the title compound as white solid (0.040 g, 0.037 mmol). MS m/z 439, 441 (M+H); 1H NMR (CD3OD, 300 MHz) δ8.20 (br, 1H), 8.10 (s, 1H), 8.08 (d, 1H), 7.60 (d, 1H), 7.53 (d. 1H), 7.35 (d, 1H), 7.21 (d, 1H), 7.07 (d, 1H), 6.82 (d, 1H), 5.27 (m, 1H), 3.88 (s, 2H), 3.60-3.50 (m, 4H), 3.30 (d, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:22](=[O:23])[CH2:21][Cl:20])[CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: O=C(Cl)CCl
Reactant: O=C1NCCNC1c1cccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NCCN(C(=O)CCl)C1c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18.2 g (0.1 mol) of 3-(2-thienyl)-piperazin-2-one, prepared in accordance with Example 16, are dissolved in 150 ml of chloroform and 11.1 g (0.11 mol) of triethylamine and 12.4 g (0.11 mol) of chloroacetyl chloride are added. The mixture is stirred for 4 hours at room temperature, the reaction solution is concentrated in vacuo and the residue is stirred with water and ethyl acetate. The ethyl acetate solution is separated off, dried and evaporated in vacuo.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][CH2:10][CH2:11][P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.BrCCBr.[OH-:35].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[P:7]([CH2:8][CH2:9][CH2:10][CH2:11][P:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:35])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: [OH-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: BrCCBr
Solvent: ClCCl
Product: O=P(CCCCP(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of palladium acetate (10 mg; 4.45×10-2 mmol), dppb (4.00 g; 9.4 mmol), 1,2-dibromoethane (3.6 g; 19.15 mmol), and dichloromethane (10 mL) was stirred for 30 minutes. To this suspension, aqueous NaOH (20% by weight; 10 mL) was added and the mixture was vigorously stirred at room temperature for 3 days. Dichloromethane (30 mL) was added, the organic phase was filtered through a silica plug which was then washed with 80 mL of CH2Cl2 /AcOEt (5:3 by volume). The combined organic solutions were evaporated to dryness. The solid residue was dissolved in boiling CH2Cl2 (ca. 30 mL) and the solution was treated with ether (100 mL; portionwise) and left at room temperature for 2 hours. Well-shaped, colorless crystals were separated, washed with ether, and dried under vacuum. The yield was 3.33 g (80%). 1H NMR (CDCl3, 20° C.), δ: 1.5 (m, 2H, CH2); 1.7 (m, 2H, CH2); 2.0 (m, 2H, CH2); 2.2 (m, 2H, CH2); 7.2-7.8 (m, 20H, Ph). 31P NMR (CDCl3, 20° C.), δ: -15.5 (s, 1P, PPh2); 32.2 (s, 1P, P(O)Ph2).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:15])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+]>CO.O.[Cl-].[Ti+3].[Cl-].[Cl-]>[C:1]([NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1c(N)cccc1Cl
Reaction time: 2 h

Procedure:
A solution of titanium (III) chloride (10 wt. % in 20-30% hydrochloric acid, 120 ml, 78 mmol) was added drop wise to a solution of tert-butyl-(2-chloro-6-nitrophenyl)-amine from Example 12A (5.7 g, 25 mmol) and sodium acetate (112 g, 1.4 moles) in methanol (205 ml) and water (63 ml). The mixture was stirred for 2 h, water was added to dissolve remaining solids and the organic solvent was evaporated. The mixture was neutralised with solid sodium hydrogen carbonate and extracted with EtOAc. The organic extracts were dried and evaporated to afford an orange oil; yield 4.7 g, 94%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([N+:22]([O-])=O)[CH:9]([OH:21])[CH2:10][O:11][CH2:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[NH2:22][CH:8]([CH:9]([OH:21])[CH2:10][O:11][CH2:12][C:13]1[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:25]
Reactant: CC(C)(C)OC(=O)CC(C(O)COCc1c(Cl)cccc1Cl)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(N)C(O)COCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
A mixture of 5-(2′,6′-dichlorobenzyloxy)-4-hydroxy-3-nitropentanoic acid t-butyl ester (2.213 g, 0.0056 mol) and wet Raney nickel (3.4 g) in methanol (150 mL) was stirred for 2 hours under a hydrogen balloon at room temperature. The reaction mixture was filtered through Celite and the filter cake was washed with methanol. The filtrate was concentrated and chased with methylene chloride to give the title product (2.078 g, 100%). TLC: (methanol/methylene chloride 1/9): Rf=0.21.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=O)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ccc(O)c(C(=O)OC)c1

Procedure:
Methyl 5-acetylsalicylate (10.0 g) was hydrogenated in the presence of 5% Pd-C (1.0 g) in ethyl acetate (200 ml) containing 70% HClO4 (2 ml) at room temperature under usual pressure of H2 gas with stirring. The catalyst was filtered off and the filtrate was evaporated in vacuo to give crude methyl 5-ethylsalicylate as pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:19].C(N(CC)CC)C.Cl>C(O)CCC.C(O)C>[ClH:12].[CH2:18]([O:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][N:27]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([Cl:12])[CH:10]=3)[N:5]=2)[CH2:26][CH2:25]1)[CH3:19]
Reactant: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Reactant: CCOCCOC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: CCO
Product: CCOCCOC1CCN(c2nc(N)c3cc(Cl)c(OC)c(OC)c3n2)CC1

Procedure:
4-Amino-2,6-dichloro-7,8-dimethoxyquinazoline (4.9 g.), 4-(2-ethoxyethoxy)piperidine (3.2 g.) and triethylamine (10 ml.) in n-butanol (400 ml.) are heated at reflux overnight under an atmosphere of nitrogen. The mixture is then cooled, evaporated in vacuo, and the residue basified (aqueous Na2CO3) and extracted 3 times with chloroform. The combined chloroform extracts are evaporated and the residue chromatographed on neutral alumina to give the crude product which is converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][CH3:19])[CH:12]=2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:3]=1[CH3:32].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH3:35])[CH3:19])[CH:12]=2)[C:5](=[O:20])[N:4]([CH2:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:3]=1[CH3:32]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNCc1cccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
A stirred solution of benzyl 2-[3-chloro-2-methyl-5-(3 [(methylamino)methyl]phenethylamino)-6-oxo-1(6H)-pyrazinyl]acetate (preparation 19) (0.38 g, 0.83 mmol) in CH2Cl2 (10 ml) was treated with formaldehyde (0.31 ml). After stirring at room temperature for 45 mins, the resultant cloudy -mixture was treated with sodium triacetoxyborohydride (253 mg, 1.19 mmol) and stirred at room temperature for a further 2 days. The reaction mixture was diluted with CH2Cl2 (200 ml) and washed with sat. aq NaHCO3, sat aq brine and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a crude solid which was purified by chromatography (SiO2, gradient elution with 100% CH2Cl2; 95:5 CH2Cl2:MeOH; 90:10 CH2Cl2:MeOH) to give the desired product (0.30 g, 77%). 1H NMR (CDCl3) δ 2.20 (s, 3H), 2.25 (s, 6H), 2.90 (t, 2H), 3.40 (s, 2H), 3.70 (m, 2H), 4.80 (s, 2H), 5.20 (s, 2H), 6.10 (m, br, 1H), 7.10-7.20 (m, 3H), 7.25 (m, 1H), 7.35 (m, 5H). LRMS m/z=469.2, 471.2 (M+1).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:26][N:25]=[C:24]([CH3:27])[N:23]=1)C1C=CC=CC=1>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[O:26][N:25]=[C:24]([CH3:27])[N:23]=1
Reactant: Cc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1noc([C@@H]2CC[C@@H]3CN2C(=O)N3O)n1
Reaction time: 4 h
Yield: 32.3 %

Procedure:
BCl3 (1M DCM solution, 2.5 mL, 2.5 mmol) was added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (130 mg, 0.414 mmol) in dry DCM (12 mL) at −78° C. The mixture was stirred at −78° C. to 0° C. for 4 hrs. The reaction mixture was then quenched with MeOH (2 mL). The solvent was removed and the residue was purified by silica gel column chromatography (0 to 10% MeOH/DCM) to afford (2S,5R)-6-hydroxy-2-(3-methyl-1,2,4-oxadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (30 mg, 32%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[Br:19]N1C(=O)CCC1=O>C(#N)C>[Br:19][C:7]1[O:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:12][CH:13]=2)=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: ClCCCOc1ccc(-c2nc(CCl)co2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: ClCCCOc1ccc(-c2nc(CCl)c(Br)o2)cc1

Procedure:
A solution of 4-(chloromethyl)-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole ax57 (0.5 g, 1.75 mmol, 1 eq) and N-bromosuccinimide (0.31 g, 1.75 mmol, 1 eq) in acetonitrile (16 ml) is stirred at 22° C. for 30 minutes. A heavy white precipitate forms during the reaction. The suspension is then filtered, the solid is washed with the minimum amount acetonitrile, collected and dried under vacuum at 40° C. to yield 290 mg of the title compound. The acetonitrile solution is concentrated to half its original volume to yield an additional 110 mg of 5-bromo-2-[4-(3-chloropropoxy)-phenyl]-4-chloromethyl-oxazole i89.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][N:5]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][CH:8]=2)[C:4](=[O:18])[CH2:3]1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:5]4[CH2:6][C:2]([CH3:1])([CH3:19])[CH2:3][C:4]4=[O:18])=[CH:17][CH:16]=3)=[O:13])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: CCOC(=O)c1ccc(N2CC(C)(C)CC2=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)CC4=O)cc3)CC2)c(C)c1
Yield: 65.8 %

Procedure:
Using ethyl 4-(4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoate (131 mg) described in Preparation Example 49 and 1-(3,5-dimethylpyridin-2-yl)piperazine (96 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (134 mg) was obtained.
Reaction SMILES: [CH2:1]([CH:4]([CH2:17][CH2:18][CH3:19])[CH2:5][O:6][C:7]1[N:12]=[C:11]([C:13]([O:15]C)=O)[CH:10]=[CH:9][CH:8]=1)[CH2:2][CH3:3].[CH3:20][C:21]#[N:22]>>[O:15]=[C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:17][CH2:18][CH3:19])[N:12]=1)[CH2:20][C:21]#[N:22]
Reactant: CC#N
Reactant: CCCC(CCC)COc1cccc(C(=O)OC)n1
Product: CCCC(CCC)COc1cccc(C(=O)CC#N)n1

Procedure:
CH3CN addition to methyl 6-((2-propylpentyl)oxy)picolinate following the method used in Example 6 gave 3-oxo-3-(6-((2-propylpentyl)oxy)pyridin-2-yl)propanenitrile in quantitative yield as a solid which was directly used in next reaction without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:11]#[C:12][Si](C)(C)C)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:4][C:5]1[C:6]([C:11]#[CH:12])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccnc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ncccc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 2-((trimethylsilyl)ethynyl)pyridin-3-yl acetate (9.5 g, 41 mmol) in THF (200 mL) was added water (25 ml). The reaction was cooled to 0° C. and TBAF (1M, 45 ml, 45 mmol) was added. The mixture warmed to ambient temperature and stirred for 1 hour. Water (100 mL) was added and the volume was reduced by half. The product was extracted into ether (3×100 mL), washed with brine and dried over MgSO4. The solution was concentrated in vacuo to afford 2-ethynylpyridin-3-yl acetate (5.5 g, 34 mmol) as a light brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(=O)(O)(O)O>[Cl-].[Zn+2].[Cl-].O>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1CCl
Reactant: c1ccccc1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 5 h
Yield: 86.6 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 200 parts of benzene is added to a mixture of 170 parts of 85 per cent strength by weight phosphoric acid, 22 parts of water and 75 parts of zinc chloride at 75° to 80° C, whilst stirring thoroughly. After a further 5 hours, the organic phase is separated off and 78 parts (86.6% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated by fractional distillation.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:42](Cl)[O:43][CH3:44]>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:42][O:43][CH3:44])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 39 mg, 0.090 mmol) in CH2Cl2 (2.0 ml) was added i-Pr2NEt (47 μl, 0.27 mmol) and MOMCl (35 μl, 0.45 mmol). The reaction was stirred at room temperature for 4 h, and was purified directly by PTLC on silica gel (30% EtOAc-hexanes) to yield the title compound as a white solid.