Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].[NH2:25][CH:26]1[C:43](=[O:44])[N:28]2[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]3[S:36][CH:37]=[N:38][N:39]=3)[CH2:31][S:32][C@H:27]12>>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:25][CH:26]2[C:43](=[O:44])[N:28]3[C:29]([C:40]([OH:42])=[O:41])=[C:30]([CH2:33][S:34][C:35]4[S:36][CH:37]=[N:38][N:39]=4)[CH2:31][S:32][C@H:27]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Yield: 86.2 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.8 g.) were treated in a similar manner to that of Example 20-(1) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.15 g.).
Reaction SMILES: [CH2:1]([N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:15][CH3:16])[CH:7]=[C:8]([O:13]C)[CH:9]=2)[CH2:4]1)[CH3:2].C(=O)([O-])O.[Na+]>Br>[CH2:1]([N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:15][CH3:16])[CH:7]=[C:8]([OH:13])[CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2cc(OC)cc(OC)c2C1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN1CCc2cc(O)cc(OC)c2C1
Temperature: 65 °C

Procedure:
A mixture of 2-ethyl-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline (280 mg, 1.27 mmol) in 48% aqueous hydrobromic acid (3 mL) was heated at 65° C. for 24 h. The mixture was added to saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant solid was purified by flash chromatography (silica, 12 g column, ISCO, 0-20% (2N ammonia in MeOH) in DCM) to afford the title compound as an off white solid (153 mg, 58%). 1H NMR (CDCl3, 300 MHz): 6.11 (d, J=2.2 Hz, 1H), 5.93 (d, J=2.2 Hz, 1H), 3.67 (s, 3H), 3.55-3.49 (m, 2H), 2.72-2.58 (m, 6H), 1.21 (t, J=7.2 Hz, 3H). LCMS (Method B): RT=1.58 min, M+H+=208.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[C:9]([Br:16])[CH:8]=1)=[O:6].CO>O>[Br:16][C:9]1[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: COC(=O)c1cc(Br)c2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)c2cc[nH]c2c1
Reaction time: 2.5 h

Procedure:
A solution of sodium hydroxide (14.08 g, 352.1 mmol) in water (100 mL) was added a to a solution of 4-bromo-1H-indole-6-carboxylic acid methyl ester in methanol (14.91 mL, 58.7 mmol) at room temperature and stirred for 2.5 hours. The reaction mixture was concentrated in vacuo, 1N HCl was added, and the product was extracted with ethyl acetate to give 13.0 g of 4-bromo-1H-indole-6-carboxylic acid, which was used in the next step with no further purification. 1H NMR (400 MHz, CD3OD) δ 8.13 (t, J=1.0 Hz, 1H), 7.87 (d, J=1.3 Hz, 1H), 7.53 (t, J=3.4 Hz, 1H), 8.13 (d, J=4.2 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.[OH-].[Na+]>C(O)C.Cl>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:11]2[O:10][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][C:4]=3[CH3:20])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:22]1
Reactant: CCOC(=O)C1=C(Nc2ccc(O)cc2C)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(O)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 66.7 %

Procedure:
To a solution of ethyl 2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.37 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.063 g, 0.43 mmol) in ethanol (2.5 mL), 2M hydrochloric acid in ethanol (0.46 mL, 0.92 mmol) was added at ambient temperature. The mixture was refluxed for 2.5 days. Cooled with ice bath, 2M sodium hydroxide solution (0.46 mL, 0.92 mmol) was added dropwise to neutralize, and ethanol (11 mL) was added and the mixture was refluxed for further 40 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.10 g, y. 70%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[N+:11]([O-])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N:24]=[N+:25]=[N-:26])(C)C.CN(C)C(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[N:24]([C:12]1[N:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[N+:25]=[N-:26]
Reactant: COC(=O)c1c(OCc2ccccc2)ccc[n+]1[O-]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(N=[N+]=[N-])ccc1OCc1ccccc1
Temperature: 0 °C
Yield: 319.8 %

Procedure:
To an acetonitrile (70 ml) solution of 10 g (38.57 mmol) of methyl 3-benzyloxypicolinate N-oxide in a 200 ml round bottomed flask, 8.9 g (7.7 mmol) of trimethylsilylazide and 4.1 g (38.57 mmol) of N,N-dimethylcarbamoyl chloride were added, and the mixture was refluxed for 12 hours. Then, 4.4 g (38.5 mmol) of trimethylsilylazide and 2.1 g (19.3 mmol) of N,N-dimethylcarbamoyl chloride were further added, and the mixture was refluxed for 12 hours. After cooling, the reaction mixture was gradually added to an ice-cooled saturated sodium hydrogen carbonate aqueous solution. Formed crystals were collected by filtration, washed with water, then dissolved in dichloromethane, dried and concentrated, and then recrystallized from ethanol to obtain 7.0 g (yield: 64%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[C:9]([CH3:20])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]1[CH:22]=[CH:23][C:24]2N(O)N=[N:27][C:25]=2[CH:26]=1.NC1C=CC=CC=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:27][C:25]4[CH:26]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:17])=[CH:18][CH:19]=3)=[C:9]([CH3:20])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(C(=O)Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A suspension of Example 66B (89 mg, 0.31 mmol) and HOBT (46 mg, 0.35 mmol) in DMF (4 mL) at room temperature was treated with aniline (0.029 mL, 0.31 mmol), NMM (0.086 mL, 0.78 mmol) and EDC.HCl (66 mg, 0.34 mmol), stirred overnight, and partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic extracts ware washed with water, and brine, dried (Na2SO4), filtered, and concentrated to a volume of about 3 mL. The product was treated with hexanes and the resulting precipitate was collected by filtration to provide 84 mg (75%) of the desired product. MS(ESI(+)) m/e 361 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H); 8.30 (s, 1H); 8.12 (d, J=8.4 Hz, 2H); 7.80 (d, J=7.5 Hz, 2H); 7.58 (d, J=8.4 Hz, 2H); 7.37 (t, J=7.5 Hz, 2H); 7.12 (t, J=7.5 Hz, 1H); 2.32 (s, 3H); Anal. Calcd. for C20H16N4OS.0.1C4H8O2: C, 66.36; H, 4.59; N, 15.17. Found: 66.07; H, 4.76; N, 15.32.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:31]([C:39]1[CH:44]=[CH:43][C:42]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:41][CH:40]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(c1ccccc1)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(C(=O)c2ccccc2)cc1
Yield: 65 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-benzoylphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (65% yield); 1H-NMR (d6-DMSO) 1.11 (9H, s), 3.71 (2H, t), 4.15 (2H, t), 6.65 (1H, s), 7.37-7.39 (2H, m), 7.57-7.59 (2H, m), 7.68-7.71 (5H, m); MS ES(+) 366.2 (M++1); Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 71.95; H, 6.24; N, 9.98. IR λmax=1695, 1645, 1604, 1360 cm−1.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16](F)[CH:15]=[C:14]([C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[C:13]=2[CH3:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(C(NC2C=CC=C(C3C4C=C(C5CCC(=O)CC=5)NC=4N=CN=3)C=2C)=O)=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]3[C:20]4[CH:27]=[C:26]([C:28]5[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH:29]=5)[NH:25][C:21]=4[N:22]=[CH:23][N:24]=3)[C:13]=2[CH3:35])=[O:10])=[CH:36][CH:37]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCC(O)CC3)cc12
Agent: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCC(=O)CC3)cc12
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]c(C3=CCC(O)CC3)cc12

Procedure:
Example 66 was prepared analogue to Example 28 step 2 by replacing Intermediate 19 in with Intermediate 55.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23](O)=[O:24])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH3:31][NH2:32]>>[CH3:31][NH:32][C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)[CH:21]=1)=[O:24]
Reactant: COc1ccc(C(=O)O)cc1Oc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN
Product: CNC(=O)c1ccc(OC)c(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1

Procedure:
The title compound was prepared from 3-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-4-(methyloxy)benzoic acid (E266, Step 2) and methylamine using the method of Example 264, Step 5; MS (ES+) m/e 327 [(M+H)—CO2tBu]+.
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14]COCC)[C:7]=1[CH3:19])C.Cl.O>CO>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[C:7]([CH3:19])[C:8]=1[OH:14]
Reactant: CCOCOc1ccc(OC)c(OCOCC)c1C
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(O)c(C)c1O
Yield: 98 %

Procedure:
A solution of 5a (910 mg, 3.37 mmol) in MeOH (28.0 mL) at room temperature was treated dropwise with 3 M HCl (9.00 mL, 26.9 mmol), then heated to reflux for one hour. Water (30 mL) was added and the solution was extracted with EtOAc (3×30 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 6a as a red amorphous solid (509 mg, 98%): 1H NMR (Acetone-d6, 500 MHz) δ 7.68 (s, 1H), 7.24 (s, 1H), 6.60 (d, J=11 Hz, 1H), 6.29 (d, J=11 Hz, 1H), 3.74 (s, 3H), 2.09 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 144.7, 142.1, 139.7, 115.6, 110.2, 108.6, 55.6, 7.6; IR (film) νmax 3583, 2920, 2359, 1616, 1259, 1090, 1020, 798 cm−1.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:14])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:28]([O:27][C:25]([N:14]=[C:10]([O:11][CH2:12][CH3:13])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=N)Cc1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)N=C(Cc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
Ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (1.6 g, 7.4 mmol) was suspended in hexanes (18.5 mL) and DCM (18.5 mL) at 0° C. 2,4,6-collidine (3.9 mL, 29.6 mmol) and ethyl chloroformate (1.6 g, 14.8 mmol) were added sequentially and the reaction mixture was allowed to warm to RT and stirred for 12 h. The solvent was removed in vacuo and the residue was suspended in EtOAc (100 mL) and sonicated for 10 minutes. The solids were removed by filtration through a pad of diatomaceous earth and the filter cake was washed with EtOAc (3×10 mL). The combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-(4-fluorophenyl)acetimidate (0.99 g, 52.7%) as an amorphous yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (dd, J=8.5, 5.6 Hz, 2H), 7.13 (t, J=8.8 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.15 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH2:11][SH:12].II.[I-].[K+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([S:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)CS
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CSc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of indole (3.00 g, 25.6 mmol) and methyl thioglycolate (2.40 mL, 25.6 mmol) in methanol:water (80 mL:20 mL) was added iodine (6.50 g, 25.6 mmol) and potassium iodide (4.25 g, 25.6 mmol). The reaction mixture was stirred at ambient temperature for 60 hours. Methanol was removed in vacuo and the aqueous layer diluted with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated in vacuo and the resulting residue was purified on a silica gel column (0-100% ethyl acetate:hexanes over 33 min) to afford the desired product. LCMS>99% at 254 nm, RT=1.29 min, m/z=222 (M+1).
Reaction SMILES: CS(O[CH2:6][C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)([CH2:10]3)[CH2:8]2)(=O)=O.C([O-])([O-])=O.[K+].[K+].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CN(C=O)C.O>[CH3:21][C:16]1([C:9]23[CH2:10][CH:11]4[CH2:15][C:7]([CH2:6][N:28]5[CH:32]=[N:31][CH:30]=[N:29]5)([CH2:14][CH:13]2[CH2:12]4)[CH2:8]3)[O:17][CH2:18][CH2:19][O:20]1
Reactant: c1nc[nH]n1
Reactant: CC1(C23CC4CC2CC(COS(C)(=O)=O)(C4)C3)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C23CC4CC2CC(Cn2cncn2)(C4)C3)OCCO1
Temperature: 110 °C
Yield: 83.9 %

Procedure:
A stirred mixture of [3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methyl methanesulfonate (2.4 g, 7.5 mmol) [as obtained from preparation 2], K2CO3 (4.5 g, 34.2 mmol), and 1,2,4-triazole (1.5 g, 22.5 mmol) in DMF (30 mL) was heated to 110° C. for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethylacetate. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain 1-{[3-(2-Methyl-1,3-dioxolan-2-yl)tricyclo[3.3.1.03,7]non-1-yl]methyl}-1H-1,2,4-triazole (1.82 g) as a viscous liquid in 85% yield. m/z (M+1) 290; IR cm−1 2932, 1668, 1506, 1441, 1373, 1311, 1211, 1140, 1047, 876, 753. 1H NMR (CDCl3) 300 MHz δ 7.99 (s, 1H), 7.93 (s, 1H), 4.07 (s, 2H), 4.03-3.92 (m, 4H), 2.42-2.32 (m, 2H), 1.86-1.79 (m, 1H), 1.74-1.65 (m, 2H), 1.52-1.37 (m, 8H), 1.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]2[C:9]([C:10]3[CH:11]=[C:12](O)[N:13]=[N:14][C:15]=3[CH2:16][O:17]2)=[CH:8][CH:7]=1)=[O:4].C(OCC)(=O)C.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:12]1[N:13]=[N:14][C:15]2[CH2:16][O:17][C:18]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:26])([CH3:25])[CH3:1])[C:19]=3[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1nnc(O)cc1-2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1nnc(Cl)cc1-2
Temperature: 95 °C

Procedure:
A suspension of methyl 7-(2,2-dimethylpropionylamino)-3-hydroxy-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (Intermediate 9, 1.12 g) in phosphoryl chloride (10 mL) was stirred and heated at 95° C. for 45 minutes. After cooling, the mixture was poured into a mixture of ice and ethyl acetate. The organic phase was washed with water and sodium bicarbonate solution, dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 3-chloro-7-(2,2-dimethylpropionylamino)-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (1.02 g) as a light coloured solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:26][C:25]3[C:17]([F:16])=[C:18]([C:22]([F:27])=[CH:23][CH:24]=3)[C:19]([NH2:21])=[O:20])[N:4]=2)=[CH:10][CH:11]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CBr
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(Cl)cc2)nc1COc1ccc(F)c(C(N)=O)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.3 %

Procedure:
To a solution of 4-Bromomethyl-2-(4-chloro-phenyl)-5-methyl-oxazole (0.12 g, 0.42 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.072 g, 0.42 mmol) and potassium carbonate (0.203 g, 1.20 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.01 g, 6%). 1H NMR (DMSO-d6, 400 MHz): δ 2.49 (s, 3H), 5.09 (s, 2H), 7.11 (m, 1H), 7.38 (m, 1H), 7.60 (d, J=8.40 Hz, 2H), 7.85 (br s, 1H), 7.95 (d, J=8.40 Hz, 2H) and 8.13 (br s, 1H). MS ES+ (379.25), HPLC (method I) Rt=16.71 min.
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8]([C:10]([F:13])([F:12])[F:11])=[O:9])=[C:6]([N:14]=[CH:15]OCC)[N:5]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:4]=1)#[N:2].[BH4-].[Na+].C(O)(=O)C>C(O)C>[C:1]([C:3]1[C:7]([S:8]([C:10]([F:11])([F:12])[F:13])=[O:9])=[C:6]([NH:14][CH3:15])[N:5]([C:19]2[C:20]([Cl:30])=[CH:21][C:22]([C:26]([F:28])([F:27])[F:29])=[CH:23][C:24]=2[Cl:25])[N:4]=1)#[N:2]
Reactant: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 10 °C
Reaction time: 6.75 h
Yield: 23.3 %

Procedure:
A 50 L reactor was charged with 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-ethoxymethylideneamino-4-trifluoromethylsulfinylpyrazole (1.645 g, 3.335 moles) and absolute ethanol (16 L) under nitrogen. The solution was cooled to 10° C., and sodium borohydride (266 g, 7.03 moles) was added slowly such that the temperature remained generally below 35° C. After 6.75 h, some additional sodium borohydride (25 g, 0.66 moles) was added and stirring was continued overnight. Acetic acid (1.3 L, 22.7 moles) was added to quench, followed by 16 L of water. The resulting precipitate was collected by filtration, washed with water, and air-dried. Recrystallization from methanol afforded 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfinylpyrazole (350 g) as an off-white solid. (m.p. about 227° C.)
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:3][C:4]([O:6][CH3:7])=[O:5].[OH:19][CH2:20][CH:21](CO)[OH:22].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:3][C:4]([O:6][CH2:7][CH:20]([CH2:21][OH:22])[OH:19])=[O:5]
Reactant: COC(=O)C=C(C)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CC(=O)OCC(O)CO)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
0.90 g (3.5 mmol) of methyl 3,7,11-trimethyldodec-2-enoate was slowly added dropwise to a solution of 0.59 g (6.4 mmol) of glycerol and 0.88 g (6.4 mmol) of potassium carbonate in dry N,N-dimethylformamide (3 mL) at 100° C. After the reaction mixture was stirred at 100° C. for 18 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 318 mg of the title compound (29% yield) as a colorless viscous product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22](O)=[O:23].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:20])([F:19])[F:21])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22]([N:56]1[CH2:57][CH2:58][N:53]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=2)[CH2:54][CH2:55]1)=[O:23]
Reactant: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Reactant: c1ccc(N2CCNCC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.50 g (4.36 mmol) of the compound of Example 4A is dissolved in 30 ml of DMF and mixed with 1.82 g (5.66 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 266 mg (2.18 mmol) of 4-dimethylaminopyridine. After adding 925 mg (5.66 mmol) of 1-(pyridin-2-yl)-piperazine, it is allowed to stir for 4 hours at room temperature. The reaction mixture is purified by RP-HPLC.