Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C([O:51][C:52](=[O:55])[CH2:53]Br)(C)(C)C.C1(C)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:53][C:52]([OH:55])=[O:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOCOCC
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride and 11.22 g of potassium-t-butoxide (100 mmol) in 500 ml of diethoxymethane is cooled to 0° C. At 0° C., 29.3 g (150 mmol) of bromoacetic acid-tert-butyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for 0.5 hour at 0° C. 250 toluene is added, the organic phase is separated, and the aqueous phase is extracted twice with 150 ml of toluene. The solvent of the combined organic phases is washed with water, dried on sodium sulfate, dessicant is filtered off, and it is distilled off in a vacuum. The residue is taken up in 400 ml of methanol. 50 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for 0.5 hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of dichloromethane, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=1[F:28])=[O:9])=C>CO.ClCCl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]2[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][C:21]=1[F:28])=[O:9]
Reactant: C=COCCONC(=O)c1ccn2cncc2c1Nc1ccc(SC)cc1F
Solvent: ClCCl
Solvent: CO
Product: CSc1ccc(Nc2c(C(=O)NOCCO)ccn3cncc23)c(F)c1
Yield: 51.1 %

Procedure:
8-(2-Fluoro-4-methylsulfanyl-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (2-vinyloxy-ethoxy)-amide (160 mg, 0.40 mmol) was dissolved in methanol and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to give a residue, which was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane) to afford the title compound as a pale yellow solid (77 mg, 51%). LCMS (method A): RT=5.96 min, [M+H]+=377. 1H NMR (DMSO-d6) 11.54 (1 H, s), 10.51 (1 H, s), 8.29 (1 H, d, J=0.80 Hz), 7.80 (1 H, dd, J=7.37, 0.94 Hz), 7.24-7.16 (2 H, m), 7.06 (1 H, dd, J=8.38, 2.11 Hz), 6.80-6.74 (1 H, m), 6.39 (1 H, s), 4.70 (1 H, s), 3.86 (2 H, t, J=4.95 Hz), 3.57 (2 H, t, J=4.95 Hz), 2.49 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.FC(F)(F)S(O[C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[Br:26])(=O)=O>>[Br:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[CH:18]=[N:17][C:16]([NH:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[CH:25]2
Reactant: N#Cc1cnc(N)cn1
Reactant: O=S(=O)(Oc1cc2cccc(Br)c2cn1)C(F)(F)F
Product: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Synthesis 5-1 using 2-amino-5-cyanopyrazine in place of (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile and 8-bromoisoquinolin-3-yl trifluoromethanesulfonate in place of 3,8-dichloroisoquinoline. 1H NMR (DMSO, 400 MHz) δ 11.30 (br s, 1H), 9.40 (s, H), 8.95 (s, H), 8.80 (s, H), 8.60 (s, H), 8.05 (d, 1H, J=8.5 Hz), 7.95 (d, 1H, J=7.5 Hz), 7.75 (dd, 1H, J=8.5 Hz, 7.5 Hz). LC-MS (2) Rt=3.21 min, m/z (ESI+) 326 & 328 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH2:9]N3C(=O)C4=CC=CC=C4C3=O)[O:6][N:5]=2)[CH2:3][CH2:2]1.C1C=C2C(N(CC(O)=O)C(=O)C2=CC=1)=O.C1(C(=NO)N)CC1.CNN.[NH2:46][CH2:47][N:48]1[CH2:52]ON=[C:49]1C1CC1>CN(C=O)C.C(N1C=CN=C1)(N1C=CN=C1)=O.ClCCCl>[CH:1]1([C:4]2[N:8]=[C:7]([CH2:9][C:47]([N:48]([CH3:52])[CH3:49])=[NH:46])[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(C2CC2)no1
Reactant: NCN1CON=C1C1CC1
Agent: CNN
Agent: NC(=NO)C1CC1
Agent: O=C(O)CN1C(=O)c2ccccc2C1=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=N)Cc1nc(C2CC2)no1
Temperature: 130 °C

Procedure:
Scheme 3 describes the preparation of known starting materials. The processes for preparation of these compounds are also known or may be carried out in analogous manner to known methods. For example, N-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide is prepared by reaction of N-phthaloylglycine in DMF and 1,1′carbonyldiimidazole, and followed by the addition of cyclopropanecarboxamidoxime. The obtained N-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide is then dissolved in 1,2-dichloroethane and N-methylhydrazine is added. The obtained 4-(aminomethyl)-3-cyclopropyl-1,2,4-oxadiazole is then treated with N,N-dimethylformaldehyde diethyl acetal and heated at about 130° C. and the desired starting material (E/Z)-N′-(3-cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl-N,N-dimethyl-formamidine is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1.[C-:29]#[N:30].[Na+].O>CS(C)=O>[C:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)#[N:30]
Reactant: [C-]#N
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCCCCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 3-[2-(5-bromopentyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.753 g) and sodium cyanide (0.37 g) in dimethyl sulfoxide (12.6 ml) was stirred at room temperature for 2 hours and then at 60° C. for 1 hour. To the mixture was added water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol as an eluent to afford 3-[2-(5-cyanopentyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.75 g).
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:28][CH:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25][CH2:26][CH3:27]>>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:8]([CH2:7][CH2:6][O:5][C:39]2[CH:38]=[CH:37][C:36]([CH2:35][CH:29]([O:28][CH2:24][CH2:25][CH2:26][CH3:27])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:41][CH:40]=2)[CH2:9][CH2:10]1
Reactant: CCCCOC(Cc1ccc(O)cc1)C(=O)OCC
Reactant: CS(=O)(=O)OCCN1CCOc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OCC
Yield: 52.6 %

Procedure:
The title compound (0.4 g, 52%) was prepared as a gummy liquid from 2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethyl methanesulfonate (0.46 g; 1.78 mmol), potassium carbonate (0.98 g, 7.12 mmol) and ethyl 2-butoxy-3-(4-hydroxyphenyl)propanoate (0.47 g, 1.78 mmol) using conditions analogous to that described in preparation 2.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:44])([CH2:42][CH3:43])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12](=O)[C:13]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[CH3:14].C(=O)(O)[O-].[Na+]>>[CH2:32]([O:31][C:30](=[O:39])[NH:29][C:13]([C:12]1[NH:11][CH:10]=[C:9]([CH2:8][C:7]([CH3:6])([CH3:44])[CH2:42][CH3:43])[N:5]=1)([CH3:14])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(C)(Cc1ccc(-c2ccc(F)cn2)cc1)NC(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C)(C)Cc1c[nH]c(C(C)(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OCc2ccccc2)n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (2.53 g, 32.79 mmol) was added to an ambient temperature solution of benzyl {2-[(4,4-dimethyl-2-oxohexyl)amino]-1-[4-(5-fluoropyridin-2-yl)benzyl]-1-methyl-2-oxoethyl}carbamate (350 mg, 0.66 mmol) in xylenes (minimal volume). After stirring in a sealed tube at 160° C. for 1 hr, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 515.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([NH:13][S:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:16])=[O:15])=[CH:7][C:6]=1[O:33][CH3:34])(=O)C.Cl>C(O)C>[NH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([NH:13][S:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:16])=[O:15])=[CH:7][C:6]=1[O:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cc(OC)c(NC(C)=O)cc1OC
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cc(OC)c(N)cc1OC

Procedure:
74.3 g of the product of Stage 1 are boiled under reflux with 24.8 ml of concentrated hydrochloric acid in 500 ml of ethanol until no more starting material can be detected (approximately 4 to 6 hours). The product precipitates on cooling. It is filtered under suction and dried in vacuo over potassium hydroxide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:13]=2)[CH:8]=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:4]([F:26])[CH:5]=1
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c(Cl)cc1F

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-82, 0.300 g), pivaloyl chloride (0.3 mL), TEA (2.0 mL), dry THF (10 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.12 (s, 9H), 4.31 (d, J=6.8 Hz, 2H), 7.63-7.71 (m, 2H), 8.05-8.07 (m, 1H), 8.16 (m, 1H), 8.55 (d, J=13.2 Hz, 1H), 9.29 (s, 1H), 12.85 (s, 1H); MS (m/z): 472.41 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1)[CH3:2].Br[CH2:13][CH:14]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:23]([CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][N:7]1[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCC(CBr)CCCCCC
Reactant: CCc1nc2c([nH]1)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCCCCCCCC(CCCCCC)Cn1c(CC)nc2c1CCCC2

Procedure:
2-Ethyl-4,5,6,7-tetrahydrobenzimidazole (14.3 parts), 2-methoxyethanol (30 parts), 1-bromo-2-hexyldecane (35 parts) and sodium carbonate (5.7 parts) are stirred together and heated at 125°-135° C. below a reflux condenser for 15 hours. The reaction mixture is cooled and extracted with a mixture of toluene (150 parts) and ethyl acetate (50 parts) and the extract is washed successively with water, dilute sulphuric acid, dilute sodium hydroxide, and water, and then distilled yielding 1-(2'-hexyldecyl)-2-ethyl-4,5,6,7-tetrahydrobenzimidazole (V) (16.6 parts), b.p. 185°-200° at 0.2 mm pressure.
Reaction SMILES: CS([C:4]1[N:19]=[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[C:11]([NH2:12])[N:6]2[N:5]=1)=O.N12CCCN=C1CCCCC2.[NH:31]1[CH:35]=[N:34][CH:33]=[N:32]1>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[CH:10]=[C:11]([NH2:12])[N:6]2[N:5]=[C:4]([N:31]3[CH:35]=[N:34][CH:33]=[N:32]3)[N:19]=[C:7]2[CH:8]=1
Reactant: CS(=O)c1nc2cc(-c3ccccn3)cc(N)n2n1
Reactant: c1nc[nH]n1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cc(-c2ccccn2)cc2nc(-n3cncn3)nn12

Procedure:
The title compound, MS m/e (%):279 (M+H+,100), was prepared in accordance with the method of example 339b) from 2-methanesulfinyl-7-pyridin-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 1,8-diazabicyclo[5.4.0]undec-7-en in 1,2,4-triazole at 130° C.
Reaction SMILES: C[Li].CN(C)P(N(C)C)(N(C)C)=O.[CH3:14][C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[C:16]=1[CH:22]=[CH:23][C:24]#[C:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[CH:28][CH:27]=1.Cl[Si](C)(C)[CH3:43]>CSC.[Cu]Br.CCOCC.N1C=CC=CC=1.C1COCC1>[CH3:14][C:15]1([CH3:43])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]1/[CH:22]=[CH:23]/[C:24]#[C:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])=[O:31])=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC1=C(C=CC#Cc2ccc(C(=O)OCC[Si](C)(C)C)cc2)C(=O)CCC1
Agent: [Cu]Br
Agent: [Li]C
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: CSC
Product: CC1(C)CCCC(=O)C1/C=C/C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A 1.3 M solution of methyllithium (3.8 mL, 5.26 mmol) was added to a stirring suspension of copper (I) bromide-dimethyl sulfide (541 mg, 2.63 mmol) and 10 mL of THF at −78° C. The solution was warmed to −40° C. over 30 minutes and then re-cooled to −78° C. Freshly distilled hexamethylphosphoramide (0.685 mL, 3.94 mmol) was added, and the solution was stirred at −78° C. for 30 minutes. A solution of (trimethylsilyl)ethyl 4-(4-(2-methyl-6-oxocyclohex-1-enyl)but-3-en-1-ynyl)benzoate (Compound D, 500 mg, 1.31 mmol), chlorotrimethylsilane (0.50 mL, 3.94 mmol) and 2.5 mL of THF was added. After the solution was stirred at −78° C. for 1 hour, pyridine (0.159 mL) and ether (0.5 mL) were added. The reaction was then quenched by the addition of 5% aqueous NaHCO3. The layers were separated and the aqueous layer extracted 3 times with ethyl acetate. The combined organic layers were washed with 10% aqueous HCl until all of the enol ether was hydrolyzed. The layers were separated and the organic layer was washed with water, and brine, and dried (MgSO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (10:1, hexane:ethyl acetate) to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17](OC)[CH2:16][CH2:15][C@H:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([C:24]#[N:25])(C)C.B(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:24]#[N:25])[CH2:16][CH2:15][C@H:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C#N
Reactant: CCOC(=O)[C@@H]1CCC(OC)N1C(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC(C#N)N1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of ethyl(2S)-N-tert-butoxycarbonyl-5-methoxyprolinate (4.10 g, 15.81 mmol) in CH2Cl2 (40 mL) at −50° C. was added trimethylsilyl cyanide (6.3 mL, 47.4 mmol) and BF3 etherate (5.60 mL, 47.4 mmol). The mixture was stirred from −50° C. to −30° C. for 2.0 h before it was quenched with saturated NaHCO3. The organic layer was separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over MgSO4. Filtration, evaporation of solvent and flash column chromatography (hexane/ethyl acetate, 3:1) gave separated cis and tran isomers (2.20 g). 1HNMR (300 MHz, CDCl3) δ isomer 1: 4.68 (dd, J=4.0, 2.0 Hz) and 4.55 (t, J=5.4 Hz) for 1H, 4.40 (t, J=7.7 Hz) and 4.26 (t, J=6.9 Hz) for 1H, 3.79 (s, 3H), 2.42–1.98 (m, 4H), 1.52 (s) and 1.44 (s) for 9 H; isomer 2: 4.78 (dd, J=8.8, 1.5 Hz) and 4.67 (d, J=8.0 Hz) for 1H, 4.45 (d, J=8.8 Hz) and 4.34 (d, J=8.0 Hz) for 1H, 3.75 (s) and 3.73 (s) for 3H, 2.56–2.12 (m, 4H), 1.52 (s) and 1.43 (s) for 9H; CIMS 255 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccncn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccncn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyrimidin-4-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.4 g, 1.21 mmol) in THF:H2O (1:1, 10 mL) at 0° C. was added LiOH (0.087 g, 3.65 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 6 hours then acidified to pH 2 with 1N HCl at 0° C. and extracted with EtOAc (2×10 mL). The organic extracts were dried and concentrated in vacuo. The residue was purified by preparative HPLC to give [1-hydroxy-4-methyl-6-(pyrimidin-4-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.3 g, 82%). 1H NMR (400 MHz, DMSO): δ 9.25 (s, 1H), 8.73 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.12 (d, J=7.2 Hz, 2H), 5.51 (dd, J=2.4, 9.6 Hz, 1H), 3.07 (dd, J=2.0, 15.2 Hz, 1H), 2.29 (s, 3H), 2.17-2.11 (m, 1H). MS (ESI) m/z=301 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC[C@@H](O)CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@@H](O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2R)-3-aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1 H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: C1(C=CC=C(O)C=1)O.ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+]([C:34]1[CH:35]=[C:36]([C:42]#[N:43])[C:37](=[CH:40][CH:41]=1)[C:38]#[N:39])([O-])=O.Cl>C1(C)C=CC=CC=1.CS(C)=O>[C:42](#[N:43])[C:36]1[C:37](=[CH:40][CH:41]=[CH:34][CH:35]=1)[C:38]#[N:39]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 175 °C
Yield: 181.2 %

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added resorcinol (26.0 g, 236 mmol), 4,4′-dichlorobenzophenone (22.8 g, 90.7 mmol), powdered anhydrous K2CO3 (48.9 g, 354 mmol), toluene (25 mL), and dimethylsulfoxide (DMSO) (500 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 170-180° C. under a nitrogen atmosphere for 6 h or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled off causing the temperature to rise in the reaction vessel to enhance the yield of the intermediate hydroxyl salt and high conversion to this intermediate. The reaction mixture was heated above 180° C. for an additional 12 h with a very small amount of toluene present to control the temperature, to totally remove the water, formed as a by-product, so that the reaction could be pushed to completion and high conversion to the hydroxyl salt intermediate. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (52.7 g, 304 mmol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile (70.6 g, 90% yield). IR [cm−1]: v 3072 (C═CH), 2234 (CN), 1586 (C═C), 1478 (aromatic), 1307 (aromatic), 1308 (C—O), 1245 (CH3), 1162 (C—O), 930 (C—O), 847 (aromatic).