Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][NH2:19].[C:20]([OH:24])(=[O:23])[CH:21]=O>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][N:19]=[CH:21][C:20]([OH:24])=[O:23]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2CON)c1Cl
Reactant: O=CC(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2CON=CC(=O)O)c1Cl
Reaction time: 16 h
Yield: 34.8 %

Procedure:
A solution in THF of O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl]hydroxylamine (0.50 g, 1.71 mmol), prepared as in step 3, and glyoxylic acid (0.18 g, 1.99 mmol) in THF was stirred for 16 hours. The solution was then diluted with aqueous citric acid and extracted with ethyl acetate (100 mL). The extract was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to yield an off white solid which was purified by chromatography on silica gel (10% methanol-chloroform). The resulting residue was crystallized from EtOAc/hexanes to provide glyoxylic acid-O-[2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethyl] oxime (0.21 g, 33%) as a white solid. mp 185°-187° C. 1H NMR (300 MHz, DMSO-d6) δ2.38 (s, 3 H), 5.17 (s, 2 H), 6.19 (d, J=7.5 Hz, 1 H), 6.82 (t, J=7.5 Hz, 1 H), 6.97 (s, 1 H), 7.09 (t, J=7.5 Hz, 1 H), 7.25 (m, 2 H), 7.44 (m, 2 H). MS (DCI/NH3) m/z 353 (M+H)+. Anal. Calcd for C16H14N2O3Cl2 ×1.0 H2O: C, 51.76; H, 4.34; N, 7.54. Found: C, 51.78; H, 3.69; N, 7.15.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]4[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[CH3:32][O:33][CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][CH:23]3[CH2:24][C@H:25]([CH3:30])[O:26][C@H:27]([CH3:29])[CH2:28]3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:35][CH2:34][O:33][CH3:32])[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C[C@@H]1CC(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCC4C[C@@H](C)O[C@@H](C)C4)n3)c(Cl)cn2)CC1
Temperature: 105 °C

Procedure:
The mixture of N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(((2R,6S)-2,6-dimethyl tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine Compound 284 (20 mg, 0.045 mmol), p-toluenesulfonic acid 2-methoxyethyl ester (14 mg, 0.06 mmol) and sodium carbonate (9.6 mg, 0.09 mmol) in 1 ml DMSO was heated in a reaction vessel at 105° C. in an oil bath for 3 h. Formation of desired product was confirmed by LCMS, MH+502/504, 0.58 min, with ˜50% conversion. Mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated. Crude product was purified by HPLC to give desired product as TFA salt. LCMS (m/z): 502.2/504.2, retention time=0.56 min.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[C:11]3[C:16]([NH:17][C:18]4[CH:27]=[CH:26][C:21]5[NH:22][C:23](=[O:25])[S:24][C:20]=5[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:28][C:7]=2[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N>O1CCCC1>[NH2:1][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2[C:11]3[C:16]([NH:17][C:18]4[CH:27]=[CH:26][C:21]5[NH:22][C:23](=[O:25])[S:24][C:20]=5[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:28][C:7]=2[CH2:6]1
Reactant: [N-]=[N+]=NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A mixture comprising 1.78 g (4.35 mmol) (RS)-6-{[7-(azidomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 19), 70 mL tetrahydrofuran and 2.54 g triphenylphosphine was stirred at 23° C. for 2 hours, 9.3 mL aqueous ammonia (25%) were added and stirring continued overnight. The solvents were removed and the residue was purified by chromatography to give 1.04 g (59%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([OH:14])[CH3:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:17](Cl)(=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20]>N1C=CC=CC=1>[C:17]([O:14][CH:12]([CH3:13])[CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=1)(=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)c1ccc(OCC(C)O)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(OCC(C)OC(=O)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.3 %

Procedure:
Cooling in an ice bath 1.1g (5 mmol) of 1-(p-ethoxycarbonyl-phenoxy)-propan- 2-ol was dissolved in 10 ml of pyridine, and 0.6 g of isovaleroyl chloride was added dropwise to this solution. The mixture was stirred at room temperature for an additional 3 hours. The reaction mixture was treated in the same way as in Example 7, and purified by column chromatography using silica gel to afford 1.6g of 1-(p-ethoxycarbonyl-phenoxy)-propan-2-ol isovalerate (compound No. 5) in a yield of 90% as a colorless oily substance having an nD32 of 1.4885. Infrared absorption: 1715, 1605, 1260, 1160, 1103, 848 (cm -1).
Reaction SMILES: CN1CCCC1=O.Cl[C:9]1[N:10]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[C:25]([CH3:31])=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.[NH:36]1[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]1>O>[NH2:30][C:27]1[N:26]=[C:25]([CH3:31])[C:24]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:9]([N:36]4[CH2:44][CH2:43][CH:39]([C:40]([NH2:42])=[O:41])[CH2:38][CH2:37]4)[N:10]3[CH2:32][CH:33]3[CH2:35][CH2:34]3)=[C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:14]=2)=[CH:29][N:28]=1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: NC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(C(N)=O)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and isonipecotamide (191 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 2.5 hours. The reaction mixture was left standing to cool followed by the addition of water and the insoluble matter was collected by filtration and dried to give the title compound (85 mg, 69%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([NH:15][NH:16][C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)(Cl)Cl>[CH2:18]([C:17]1[O:14][C:13]([C:3]2[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[C:5]([Br:12])[N:4]=2)=[N:15][N:16]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)nc1C(=O)NNC(=O)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: Nc1cc(C(F)(F)F)c(Br)nc1-c1nnc(Cc2ccccc2)o1
Temperature: 65 °C

Procedure:
To a stirred suspension of 3-amino-6-bromo-N′-(2-phenylacetyl)-5-(trifluoromethyl) picolinohydrazide (106 mg, 0.254 mmol) in CHCl3 (2 ml) was added TEA (142 ul, 1.016 mmol) followed by TsCl (145 mg, 0.762 mmol). The mixture was heated to 65° C. for 3 h. The solvent was removed in vacuo and the resulting brown residue was suspended in EtOAc (10 ml). The mixture was washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 85% iso-hexane/EtOAc to afford the title compound as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 7.85 (1H, s), 7.39 (4H, m), 7.30 (3H, m), 4.45 (2H, s). LC-MS Rt=5.84 min [M+H]+ 401.0 Method 10minLC_v002.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[N:12]=1.S(Cl)(Cl)=O.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[S:9][CH:10]=2)[CH:14]=1
Reactant: CN
Reactant: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cccc(-c2csc(-c3cnccc3C)n2)c1

Procedure:
By the reaction in the same manner as in Example 60 using 3-[2-(4-methyl-pyridin-3-yl)-1,3-thiazol-4-yl]benzoic acid (256 mg), thionyl chloride (0.09 ml) and aqueous methylamine solution (40%, 5 ml), the title compound (191 mg) was obtained as colorless powder crystals.
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][O:7][CH2:8][CH3:9])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][O:7][CH2:8][CH3:9]
Reactant: CCOCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOCC(CN)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of tert-butyl (1-azido-3-ethoxypropan-2-yl)carbamate (1.3 g, 5.4 mmol) in methanol (40 mL) was added palladium on carbon (0.13 g, 10% w/w). The mixture was stirred under a hydrogen (15 psi) atmosphere at room temperature. After 14 hours, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl (1-amino-3-ethoxypropan-2-yl)carbamate. MS ESI calc'd. for C10H23N2O3 [M+H]+ 219. found 219. 1H NMR (400 MHz, CD3OD) δ 3.93 (d, J=6.0 Hz, 1H), 3.59-3.51 (m, 3H), 3.45 (dd, J=9.7 Hz, 6.0 Hz, 1H), 3.18 (dd, J=12.8 Hz, 4.4 Hz, 1H), 2.97 (dd, J=12.8 Hz, 8.8 Hz, 1H), 1.48 (s, 9H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[NH:13][N:12]=[N:11]1.[CH3:16]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1
Reactant: COc1cccc(-n2nn[nH]c2=O)c1C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cccc(-n2nnn(C)c2=O)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-methoxyphenyl)-1,4-dihydrotetrazole-5-one 10.00 g and N,N-dimethylformamide 100 mL was added 55% sodium hydride 2.47 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 3.5 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-methoxyphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 2.19 g.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([OH:8])[CH2:6][CH2:5][O:4]1.[H-].[Na+].[CH2:11]([O:18][CH2:19][CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:11]([O:18][CH2:19][CH2:20][O:8][CH:7]1[CH2:6][CH2:5][O:4][CH:3]1[O:2][CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC1OCCC1O
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1OCCC1OCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-tetrahydro-furan-3-ol in DMF 200 mL was added sodium hydride in small portions with stirring at 0° C. for 2 hrs, then 2-Benzyloxy-ethanol was added from the dropping funnel over a period of 1 hour, the resulting mixture was stirred at 25° C. for 15 hrs, it was poured into 400 mL water, EtOAC (1 L) were added and separated. The organic layer was washed with sat. NaHCO3 (500 mL), dried over Na2SO4, filtered and concentrated, The residue was purified by column chromatography (PE:EA=5:1) to yield 10 g of 3-(2-Benzyloxy-ethoxy)-2-methoxy-tetrahydro-furan (oil).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[CH:9]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[O-].[Na+]>Cl>[CH:9]([O:22][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=Cc1ccncc1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: c1ccc(C(OCCc2ccncc2)c2ccccc2)cc1
Temperature: 135 °C
Yield: 31.6 %

Procedure:
With reference to FIG. 7, to a stirred solution of 4-vinylpyridine 1 (10 g, 95.1 mmol) and benzhydrol 2 (35.04 g, 190 mmol), was added sodium methoxide (1.541 g, 28.5 mmol). The reaction mixture was heated at 130-140° C. for 20 hrs, cooled to RT and acidified with 1 N HCl (150 ml). The solution was extracted with ethyl acetate (3×30 ml) to remove unreacted benzhydrol and side product dibenzhydryl ether. The aqueous solution was further basified with 10% NaOH solution (pH 10) and extracted with dichloromethane (3×30 ml). The combined organic layers were washed with water (2×20 ml), dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. The oily residue was subjected to vacuum distillation to remove unreacted 4-vinylpyridine (3.9 g). The product was dried under vacuum to remove trace amounts of 4-vinylpyridine to yield 8.7 g (52%) of the title compound 3. 1H-NMR (CDCl3; 400 MHz): 2.90-2.93 (t, 2H, J=6.4 Hz, OCH2CH2), 3.66-3.67 (t, 2H, J=6.8 Hz, OCH2CH2), 5.32 (s, 1H, PhCH(O)Ph), 7.13-7.14 (d, 2H, J=5.6 Hz, 3,5-Pyr-H), 7.17-7.33 (m, 10H, ArH), 8.47-8.48 (d, 2H, J=6.0 Hz, 2,6-Pyr-H).
Reaction SMILES: [C:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[O:14]CC(C)(C)N=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH2:21].[Na+].[Cl-]>O1CCOCC1>[C:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]([OH:14])=[O:21])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)COC(c2ccsc2C(=O)c2cccs2)=N1
Reactant: O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ccsc1C(=O)c1cccs1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2.8 g of 2-(2-thenoyl)-3-(4,4-dimethyl-2-oxazoline-2-yl)thiophene was added to a solution of 30 ml of concentrated hydrochloric acid, 20 ml of water and 20 ml of dioxane, and the solution was stirred at 100° C. for 8 hours. After cooling the solution, an aqueous NaCl solution was added thereto. The resultant solution was extracted with chloroform and dried. After the solvent was distilled off, the residue was purified by silica gel chromatography to obtain 0.70 g of 2-(2-thenoyl)-3-thiophene carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Br[CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CC(C)=CCBr
Product: CC(C)=CCN1C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N(c2ccccc2C)C1C

Procedure:
The title compound, MS: m/e=568.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-bromo-3-methyl-2-butene.
Reaction SMILES: [N:1]1([C:6]2[CH:30]=[CH:29][C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([N+:26]([O-])=O)=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>[Pd].CN(C)C=O>[NH2:26][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:30][CH:29]=2)=[CH:16][C:15]=1[N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1N
Yield: 69.9 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-{5-[4-(imidazole-1-yl)phenoxy]-2-nitrophenyl]-N-methylcarbamate (8.8 g), palladium on carbon (10%, 0.8 g) and N,N-dimethylformamide (160 ml) and the reaction mixture was purified to give the title compound (5.7 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@H:12]([OH:22])[C@@H:11]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCC[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@@H]1O
Yield: 99.7 %

Procedure:
To a solution of methyl (Z)-7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (25) (109.9 g, 233.5 mmol) in ethyl acetate (450 ml), 5%-palladium on carbon (10.98 g) was added and the mixture was hydrogenated at ambient pressure and at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give methyl 7-[(1R,2S,3R,5S)-2-(t-butyldimethylsilyloxymethyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (26) (110.1 g, 232.9 mmol, 99.7%) as colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=3[F:24])=[N:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][NH:29][CH2:28]1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:29]4[CH2:30][C:27]([OH:26])([C:31]([O:33][CH3:34])=[O:32])[CH2:28]4)=[CH:18][C:17]=3[F:24])=[N:13][C:12]=2[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2nc3cc(Cc4ccccc4)ccc3s2)c(F)c1
Reactant: COC(=O)C1(O)CNC1
Product: COC(=O)C1(O)CN(Cc2ccc(-c3nc4cc(Cc5ccccc5)ccc4s3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B1 and general procedure I from 4-(5-benzylbenzo[d]thiazol-2-yl)-3-fluorobenzaldehyde (0.057 g, 0.16 mmol) and methyl 3-hydroxyazetidine-3-carboxylate (0.031 g, 0.16 mmol) to give methyl 1-((4-(5-benzylbenzo[d]thiazol-2-yl)-3-fluorophenyl)methyl)-3-hydroxyazetidine-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ ppm 8.37 (t, J=7.7 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.21-7.35 (m, 8H), 4.15 (s, 2H), 3.93-4.07 (m, 7H), 3.52-3.67 (m, 2H). MS (ESI) m/z: Calculated: 462.1 Observed: 463.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:16]>O>[NH2:1][C:2]1[O:3][C:4]2[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1[C:8]([NH2:9])=[O:16]
Reactant: N#Cc1c(N)oc2ccccc2c1=O
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1c(N)oc2ccccc2c1=O

Procedure:
-- A mixture of 1.5 g of 2-amino-4-oxo-4H-1-benzopyran-3-carbonitrile and 7 ml of 80% sulfuric acid is heated for 1 hour on the steam bath. The mixture is cooled, poured into water, and the solid filtered and recrystallized from ethanol, mp 264°-6°C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.O.[OH-].[Li+]>CO.O>[C:17]1([CH2:16][CH2:15][C:14]([NH:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6]3[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=3[NH:8][CH2:9]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
(3(S)-(3-Phenylpropionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)acetic acid methyl ester (104a) was dissolved in 90% methanol. Lithium hydroxide hydrate was added to the reaction and the reaction was stirred at room temperature for 4 h. The reaction was evaporated in vacuo to give a white solid. This was dissolved in 20 ml of water and acidified to pH 5 and extracted with ethyl acetate to afford 304 mg (88%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.5-6.9 (11H, m), 4.92-4.8 (1H, m), 4.7-4.58 (1H, d), 4.38-4.25 (1H, d), 3.88-3.78 (1H, m), 3.45-3.25 (1H, m), 3.05-2.85 (2H, m), 2.55-2.45 (2H, m). 4-Oxo-3(S)-{2-[2-oxo-3(S)-(3-phenylpropionylamino)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylacetylamino}butyric acid (106a). N-[1-(2-Benzyloxy5-oxotetrahydrofuran-3-ylcarbamoyl-methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-3-phenylpropionamide was prepared from 105a by the procedure used to prepare compound H (stepA) to afford 390 mg (93%) of the product as diastereomers. 1H NMR (CD3OD) δ7.58-7.22 (14H, m), 5.78-5.73 (0.5 H, d), 5.64 (0.5 H, s), 5.0-4.72 (4H, m), 4.54-4.42 (2H, m), 3.82-3.76 (0.5 H, m), 3.68-3.62 (o.5 H, m), 3.28-3.21 (0.5H, m), 3.19-3.12 (0.5H, m), 3.07-2.98 (2H, m), 2.78-2.48 (4H, m).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[CH:11]=[N:12]/O)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.CO>CC(O)=O.[Zn]>[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:15])([CH3:14])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(/C=N/O)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)OB(O)c2cc(CN)ccc21
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of crude compound (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbaldehyde oxime (47.4 mmol) in AcOH (60 mL) at rt was added zinc dust (12.3 g, 190 mmol). The reaction mixture was stirred at 40° C. for 4 h under argon atmosphere. Methanol was added and the mixture was filtered over Celite. The filtrate was concentrated and dissolved in ethyl acetate. The organic layer was washed with water. The water layer was lyophilized to give the crude compound 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol as a light yellow solid. It was used in next step without further purification. MS: m/z=192.0 (M+1, ESI+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)nc1
Solvent: ClCCl
Product: Cc1ccc(CCl)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
A mixed solution of (5-methyl-pyridine-2-yl)-methanol (500 mg, 4.1 mmol) described in Manufacturing Example 11-1-1, thionyl chloride (0.59 mL, 8.1 mmol) and methylene chloride (10 mL) was stirred for 5 minutes under reflux. The reaction solution was cooled to room temperature and concentrated under a reduced pressure. The resulting residue was partitioned into diethyl ether and saturated sodium bicarbonate solution. The organic layer was separated and passed through a glass filter lined with silica gel (eluted with ethyl acetate). The eluate was concentrated to obtain the title compound (440 mg, 76%) as a crude product. The resulting compound was used in the following reaction without further purification.