Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C2C(=CC=C(F)C=2)C(=O)N(C)C=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.FC1C=C2C(=CC=1)C(=O)N(C)C=C2B1OC(C)(C)C(C)(C)O1.ClC1C(OCC2CC2)=CN=C(S(C)(=O)=O)N=1.[CH:71]1([CH2:74][O:75][C:76]2[C:77]([C:86]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([F:96])[CH:94]=4)[C:89](=[O:97])[N:88]([CH3:98])[CH:87]=3)=[N:78][C:79](S(C)(=O)=O)=[N:80][CH:81]=2)[CH2:73][CH2:72]1.[CH2:99]([S:101]([NH2:104])(=[O:103])=[O:102])[CH3:100]>>[CH:71]1([CH2:74][O:75][C:76]2[C:77]([C:86]3[C:95]4[C:90](=[CH:91][CH:92]=[C:93]([F:96])[CH:94]=4)[C:89](=[O:97])[N:88]([CH3:98])[CH:87]=3)=[N:78][C:79]([NH:104][S:101]([CH2:99][CH3:100])(=[O:103])=[O:102])=[N:80][CH:81]=2)[CH2:72][CH2:73]1
Reactant: CCS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2cc(F)ccc2c1=O
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CS(=O)(=O)c1ncc(OCC2CC2)c(Cl)n1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cc(F)ccc2c1=O
Product: CCS(=O)(=O)Nc1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3ccc(F)cc23)n1

Procedure:
The title compound of Example 47, step 2 was treated with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Example 89, step 1 and the resulting 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one was coupled to the title compound of Example 152, step 4 in a manner similar to Example 152, step 5 and the resulting 4-[5-(cyclopropylmethoxy)-2-methylsulfonylpyrimidin-4-yl]-6-fluoro-2-methylisoquinolin-1-one was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.04 (brs, 1H), 8.54 (s, 1H), 8.36 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 8.01 (s, 1H), 7.65 (dd, J1=11.2 Hz, J2=2.4 Hz, 1H), 7.45-7.38 (m, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.48 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H), 1.16-1.04 (m, 1H), 0.50-0.42 (m, 2H), 0.27-0.20 (m, 2H). LCMS: 433.0 (M+1)+
Reaction SMILES: [CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11]O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.COC(N=NC(OC)=O)=O>O1CCCC1.O>[CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][N:36]3[C:32](=[O:42])[C:33]4[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:35]3=[O:37])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc(C=CC2CC2)s1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C=CC2CC2)s1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
(5-(2-Cyclopropylvinyl)thiophen-2-yl)methanol described in Preparation Example 149 (930 mg, 5.19 mmol), triphenylphosphine (2040 mg, 7.78 mmol) and phthalimide (1140 mg, 7.78 mmol) were dissolved in tetrahydrofuran (50 mL), azodicarboxylic acid dimethyl ester (1140 mg, 7.78 mmol) was added under stirring at room temperature, and the solution was stirred for 1 hour. Water (50 mL) was added to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=9:1), and the title compound (330 mg, 1.07 mmol, 20.6%) was obtained as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([NH:13][NH2:14])=[O:12])([CH3:9])([CH3:8])[CH3:7]>CCCCCC>[C:6]([O:10][C:11]([NH:13][N:14]=[C:1]1[CH2:4][CH2:3][CH2:2]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1CCC1
Yield: 81.2 %

Procedure:
The reaction mixture of cyclobutanone (15 g, 214 mmol) and hydrazinecarboxylic acid tert-butyl ester (28.3 g, 214 mmol) in hexane (225 mL) was heated to reflux for 2 hours. After cooling down, a precipitate formed and the solid was filtered under vacuum. Isopropanol (10 mL) and hexane (100 mL) were added to the solid and the mixture was put on the rotary evaporator under vacuum until a slurry was generated. After filtration, the solid was washed with hexane twice and dried in vacuo to afford N′-cyclobutylidene-hydrazinecarboxylic acid tert-butyl ester (32 g, 81%) as white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH2:12])[S:10][CH:11]=2)=[CH:4][CH:3]=1.[C:13]1([C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([NH:12][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:24][CH:23]=3)(=[O:27])=[O:26])[S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nc(-c2ccc(Cl)s2)cs1
Product: O=S(=O)(Nc1nc(-c2ccc(Cl)s2)cs1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(5-chloro-2-thieny)-1,3-thiazol-2-amine and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (4.3 mg) with purity >80%. MS (pos) m/z 433.1, 435.1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]2[O:7][C@@H:8]([C:11]([OH:13])=O)[CH2:9][O:10][C:5]=2[CH:4]=1.[N:18]1[CH:23]=[C:22]([NH2:24])[CH:21]=[C:20]2[CH2:25][O:26][CH2:27][CH2:28][C:19]=12>>[N:18]1[CH:23]=[C:22]([NH:24][C:11]([C@@H:8]2[O:7][C:6]3[CH:14]=[CH:15][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:4][C:5]=3[O:10][CH2:9]2)=[O:13])[CH:21]=[C:20]2[CH2:25][O:26][CH2:27][CH2:28][C:19]=12
Reactant: Nc1cnc2c(c1)COCC2
Reactant: O=C(O)[C@H]1COc2cc(C(F)(F)F)ccc2O1
Product: O=C(Nc1cnc2c(c1)COCC2)[C@H]1COc2cc(C(F)(F)F)ccc2O1
Yield: 91.2 %

Procedure:
The compound is prepared in a similar manner as Compound 18 by condensing (R)-6-(trifluoromethyl)-2,3-dihydrobenzo[1,4]dioxine-2-carboxylic acid (38 mg, 0.15 mmol) with 7,8-dihydro-5H-pyrano[4,3-b]pyridin-3-ylamine (42 mg, 0.28 mmol) for 16 hours and purified by semi-preparative HPLC (55-75 gradient) to give the titled amide (52 mg, 89%). m/z=381.1 (M+1)4. HPLC: 9.62 min. 1H NMR (400 MHz; d6-DMSO) δ 10.38 (m, 1H), 8.52 (d, 1H, J=2.3 Hz), 7.77 (d, 1H, J=2.3 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.26-7.22 (m, 2H), 7.09 (d, 1H, J=7.7 Hz), 5.17-5.14 (m, 1H), 4.52-4.49 (m, 2H), 3.95 (t, 2H, J=5.7 Hz), 2.82 (t, 211, J=5.7 Hz).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[N:11][C:12](=[O:15])[NH:13][CH:14]=1.Cl[CH2:17][S:18][C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1.[K+].[Br-]>CN(C=O)C.C(O)(C)C.CCO>[C:21]1([CH3:25])[CH:22]=[CH:23][CH:24]=[C:19]([S:18][CH2:17][N:11]2[CH:10]=[C:9]([Cl:8])[CH:14]=[N:13][C:12]2=[O:15])[CH:20]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1cccc(SCCl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: CC(C)O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cccc(SCn2cc(Cl)cnc2=O)c1
Reaction time: 0.22 h

Procedure:
Potassium tert-butoxide (20 mmol) in DMF (12 ml) was added to a solution of 5-chloro-pyrimidin-2-one hydrochloride (10 mmol) in DMF (60 ml). After stirring for 13 min, a solution of 3-chloromethylthiotoluene (10 mmol) in DMF (12 ml) was added. The resultant mixture was stirred at 60° C. for 3 h, the solvent distilled off at reduced pressure and the residue triturated and washed well with water before drying. The product was the N- and O-alkylated isomers in the ratio 7:5; yield: 1.71 g (64%). The N-isomer was isolated by its low solubility in ether in which the O-isomer is readily soluble; m.p. 134° C. (isoPrOH/EtOH). (Found C53.73; H4.25. Calc. for C12H11ClN2OS: C54.03; H4.16) 1H NMR (DMSO-d6): δ 2.27 (Me), 5.22 (CH2), 7.17 (Ph). 8.00 and 8.56 (H-4 and H-6, J 4 Hz). IR (KBr): 1660 cm-1 (CO). MS [70 eV, m/z (% rel. int.)]: 266/268 (6/2,M) 143/145 (100/32). MS [70 eV, m/z (% rel. int.)] : 266/268 (11/4,M, 137 (100).
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9](=[O:14])C(Cl)(Cl)Cl)[CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:9]([C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[NH:8][CH:7]=1)=[O:14])[CH3:22]
Reactant: CC(=O)c1cc(C(=O)C(Cl)(Cl)Cl)c[nH]1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1c[nH]c(C(C)=O)c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 1-(5-Acetyl-1H-pyrrol-3-yl)-2,2,2-trichloro-ethanone (0.980 g, 3.85 mmol) in ethanol (10 mL), potassium carbonate (0.224 g, 1.62 mmol) was added and the mixture refluxed for 1 h. The mixture was cooled at room temperature and filtred through a celite pad washing with ethanol (50 mL). Organic solvent was evaporated to dryness and the residue dissolved in ethylacetate (15 mL) and washed with water (2×10 mL) and brine (5 mL), dried over sodium sulfate, filtered, and concentered in vacuo to give 0.567 g (81%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:13]([CH2:20][CH2:21][NH:22][C:10]([C:2]1[NH:1][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc2ccncc2[nH]1
Reactant: NCCOc1ccccc1
Product: O=C(NCCOc1ccccc1)c1cc2ccncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15) and 2-phenoxyethylamine to give the title compound as a pale yellow solid. δH (CD3OD): 3.81 (2H, t), 4.18 (2H, t), 6.89–6.97 (3H, m), 7.14 (1H, s), 7.26 (2H, t), 7.65 (1H, d), 8.10 (1H, d), 8.78 (1H, s); m/z (ES+)=282 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:1][C:2]1[C:3]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[N:13]3)=[CH:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Product: COc1ccccc1-c1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 53.5 %

Procedure:
Trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol) was coupled to 2-methoxyphenyl-boronic acid (13.5 mg, 0.089 mmol) as described in Example 35 part c), affording 5-(6-fluoro-2′-methoxybiphenyl-3-yl)-2-trifluoromethyl[1,8]-naphthyridine (14.5 mg, 53%). δH (360 MHz, CDCl3) 3.86 (3H, s), 7.03-7.09 (2H, m), 7.32-7.48 (4H, m), 7.55 (1H, dd, J 2.5 and 6.7), 7.60 (1H, d, J 4.6), 7.83 (1H, d, J 8.4), 8.66 (1H, d, J 8.4), 9.27 (1H, d, J 4.6). m/z (ES+) 399 [MH]+.
Reaction SMILES: [S:1]1[CH:6]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[S:4][CH2:3][CH2:2]1.CO.O1CCCC1.C(O)(=O)C>[C].[Pd].O>[S:1]1[CH:6]=[C:5]([C:7](=[N:33][O:34][CH3:35])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)C1=CSCCS1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1=CSCCS1
Reaction time: 4 h
Yield: 60.1 %

Procedure:
Palladium carbon (0.8 g.) was added to a mixture of 4-nitrobenzyl 7-[2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.0 g.), methanol (20 ml.), tetrahydrofuran (40 ml.), acetic acid (0.3 ml.) and water (3 ml.), and subjected to catalytic reduction under ordinary pressure at room temperature for 4 hours. After removing the catalyst from the resultant mixture by filtration, the filtrate was concentrated at 40° C. in vacuo. Ethyl acetate (20 ml.) was added to the residue, and the solution was adjusted to pH 6.5 to 7.0 with a saturated aqueous solution of sodium bicarbonate, stirred for 30 minutes and then filtered. The insoluble product was washed with water (10 ml.). The filtrate and washings were combined together, and the aqueous layer was separated washed with ethyl acetate and adjusted to pH 5.0 with 10% hydrochloric acid. The solution was treated with activated charcoal (0.1 g.) for 5 minutes and then filtered in vacuo. The filtrate was washed with diethyl ether and the organic solvent was removed by introducing nitrogen gas. The aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid under ice cooling and extracted with ethyl acetate (50 ml.) twice. The extract was washed with ice-water, dried over magnesium sulfate and filtered. The filtrate was concentrated at 40° C. in vacuo and the residue was crystallized with diethyl ether (30 ml.). The crystals were collected by filtration, washed with diethyl ether and dried to give 7-[2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), pale yellow powder.
Reaction SMILES: [OH:1]C1CCN(C2C=CC(C(OCC)=O)=CC=2)CC1.[CH2:19]1[CH2:24][CH2:23][CH:22]([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:21][CH2:20]1.CS(C)=O.N1C=CC=CC=1.C(O)(C(F)(F)F)=O>C1C=CC=CC=1.CCOC(C)=O>[C:26]([NH:25][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:1]
Reactant: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 23 °C

Procedure:
In a 200 mL round-bottomed flask, ethyl 4-(4-hydroxypiperidin-1-yl)benzoate 390A (0.878 g, 3.52 mmol), DCC (2.202 g, 10.67 mmol), and DMSO (5.0 mL, 70.5 mmol) were taken up in benzene (9.52 mL) to give a colorless solution. The mixture was then cooled in an ice/brine bath. Pyridine (0.26 mL, 3.21 mmol) and TFA (0.12 mL, 1.558 mmol) were added sequentially and in a drop-wise manner, while maintaining the reaction mixture at <5° C. Once the additions were complete, the reaction was allowed to stir at the cooler temperature and then slowly warmed to 23° C. over a 24 hr period. The reaction was diluted with EtOAc (50 mL) and stirred at 23° C. overnight. The undissolved white solid (dicyclohexylurea) was removed by filtration and rinsed with additional EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated to clear oil. The oil was triturated with hexanes and gently stirred overnight. A white solid was collected by filtration and dried in vacuo. Re-crystallization in CCl4 gave a fine solid (dicyclohexylurea impurity) that was removed by vacuum filtration. The CCl4 filtrate was concentrated to yellow oil and dried in vacuo to afford the title compound as a yellow solid (0.575 g, 66.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.07 Hz, 3H) 2.45 (t, J=6.06 Hz, 4H) 3.74 (t, J=6.06 Hz, 4H) 4.24 (q, J=7.07 Hz, 2H) 6.97-7.09 (m, 2H) 7.75-7.86 (m, 2H). ESI-MS: m/z 248.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[CH:4][C:3]=1[O:17][CH3:18].C([Mg]Cl)C.[CH3:23][N:24]1[C:28]([C:29](OC)=[O:30])=[CH:27][C:26]2[CH:33]=[CH:34][S:35][C:25]1=2>O1CCCC1.[Cl-].[Na+].O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([B:8]2[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:14])([CH3:15])[O:16]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:28]1[N:24]([CH3:23])[C:25]2[S:35][CH:34]=[CH:33][C:26]=2[CH:27]=1)=[O:30]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COC(=O)c1cc2ccsc2n1C
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccsc2n1C
Temperature: 25 °C
Yield: 32.5 %

Procedure:
To 4-amino-3-methoxyphenylboronic acid pinacol ester (1340 mg, 5.38 mmol) in tetrahydrofuran (20 ml) under a nitrogen atmosphere was added slowly a 2M solution of ethylmagnesium chloride in tetrahydrofuran (2.69 ml, 5.38 mmol) and the resulting solution was heated at reflux for one hour. Methyl 6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxylate (500 mg, 2.56 mmol) was added and the reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and poured in brine. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed subsequently with water and brine. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane with gradient of 0 to 50% of ethyl acetate). The product was dissolved in hot dichloromethane and the remaining solids were removed by filtration. The filtrate was concentrated, the residue dissolved in hot dichloromethane and diethylether was added. The formed solids were collected by filtration, washed with diethylether and dried to yield N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-methyl-6H-thieno[2,3-b]pyrrole-5-carboxamide (343 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:9]([NH:11][CH:12]2[CH2:17][CH:16]([OH:18])[CH2:15][CH2:14][CH:13]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:9]([NH:11][CH:12]3[CH:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH2:14][CH2:15][CH:16]([O:18][C:37](=[O:39])[CH3:38])[CH2:17]3)=[O:10])[CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C2CCC(O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(C2CCC(OC(C)=O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 100 °C

Procedure:
3.2 g of (±)-3,4-bis-cyclopropylmethoxy-N-[(1RS,2RS,5RS)-2-(3,4-dimethoxyphenyl)-5-hydroxycyclohexyl]benzamide (compound D1) are dissolved in 70 ml of acetic anhydride and the solution is heated to 100° C. for 5 h. The solution is concentrated and the residue is recrystallized in ethanol. 3.15 g of the title compound of m.p. 148-151° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2].[Br:17]Br>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([Br:17])=[C:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:10]=12)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1scc2c1CCC(C)(C)C2
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(Br)c2c1CCC(C)(C)C2
Temperature: 50 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester (715 mg, 3.0 mmol) in acetic acid (5 mL), bromine (480 mg, 3.0 mmol) is slowly added at rt. Upon completion of the addition, the mixture is heated to 50° C. and stirred for 4 h. The reaction is quenched by adding 1 N aq. NaOH and the mixture is extracted with DCM (3×50 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to provide crude 3-bromo-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid ethyl ester (774 mg) as a brown oil; 1H NMR (CDCl3): δ 4.27 (q, J=7.6 Hz, 2H), 2.97 (t, J=7.0 Hz, 2H), 2.26 8 s, 2H), 1.51 (t, J=7.0 Hz, 2H), 1.33 8t, J=7.6 Hz, 3H), 0.95 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([CH:20]=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[C:4]([F:30])[CH:3]=1.S(=O)(=O)([OH:33])N.Cl([O-])=O.[Na+].OP([O-])(O)=O.[K+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:33])=[O:21])=[CH:18][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[C:4]([F:30])[CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3n[nH]c4cc(Cl)cc(F)c34)cnc21
Yield: 95 %

Procedure:
2-(6-Chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (139 mg, 0.31 mmol) was dissolved in THF (4.7 ml) and water (1.6 ml) and sulfamic acid (291 mg, 3.0 mmol) was added. A solution of sodium chlorite (17 mg, 0.185 mmol) and potassium phosphate monobasic (232 mg, 1.7 mmol) in water (1.4 ml) was slowly added. After 1 h the reaction mixture was poured into ethyl acetate and water. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 136 mg of 2-(6-chloro-4-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:32]([N:36]=[C:37]=[O:38])[CH2:33][CH2:34][CH3:35]>>[CH2:32]([NH:36][C:37]([O:31][C:28]1[CH:29]=[CH:30][C:2]([NH:1][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])=[C:3]([CH:27]=1)[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12][CH2:13]1)=[O:5])=[O:38])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCN=C=O
Reactant: Nc1ccc(O)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Product: CCCCNC(=O)Nc1ccc(OC(=O)NCCCC)cc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
{2-amino-5-hydroxy-N-[(1-diphenylmethylpiperidin-4-yl)methyl]-benzamide and n-butyliso-cyanate}: mp 197°-199° C.; 1H NMR(CDCl3)ppm: 0.90 (3H, t), 1.20-1.90 (11H, m), 2.88 (2H, m), 3.18 (2H, td), 3.25 (2H, dd), 4.23 (1H, s), 5.31 (1H, bs), 6.88 (1H, dd), 6.97 (1H, d), 7.10-741 (11H, m), 7.95 (1H, d), 8.66 (1H, s), 9.40 (1H, s); and,
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=O)=[CH:11][CH:10]=1)#[N:2].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Product: COC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 28 %

Procedure:
A mixture of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-oxo-2,3-dihydrobenzimidazole-7-carboxylate (8.02 g) in phosphorus oxychloride (30 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated and the resulting residue was poured into ice-water. The mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give crystals, which were recrystallized from chloroform-methanol to afford colorless needles (2.2 g, 28%), m.p. 154-157° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:13]([NH:12][CH:10]2[CH2:9][NH:8][CH2:11]2)=[O:14])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CNC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
To a solution of 1-t-butoxycarbonyl-3-(p-nitrobenzyloxycarbonylamino)azetidine (4.84 g, 13.8 mmol) (obtained as described in Reference Example 57(3)) in 1,4-dioxane (50 ml) was added a 4N solution of hydrogen chloride in 1,4-dioxane (50 ml) in an ice bath, and the mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the resulting mixture was filtered, and the residue was washed with ethyl acetate and then dried under reduced pressure to give 3-(p-nitrobenzyloxycarbonylamino)azetidine hydrochloride (2.31 g, yield 58%) as pale yellow crystals.