Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([N:6](CC)CC)C.[Br:11][C:12]1[N:17]=[C:16]([C:18]([Cl:20])=[O:19])[CH:15]=[CH:14][CH:13]=1>C(#N)C>[ClH:20].[NH2:6][CH2:4][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:11])[N:17]=1)=[O:19]
Reactant: O=C(Cl)c1cccc(Br)n1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cl
Product: NCC(=O)c1cccc(Br)n1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Magnesium chloride (21.30 g, 224 mmol) and triethylamine (62 ml, 446 mmol) were sequentially added to a suspension of 2-tert-butoxycarbonylamidomalonic acid monoethyl ester (50.30 g, 203 mmol) in acetonitrile (300 ml) under Ar atmosphere while ice-cooled and the mixture was stirred for 1 hour. Subsequently, a solution of 6-bromopyridine-2-carbonyl chloride (37.40 g, 170 mmol) in acetonitrile (150 ml) was added dropwise at the same temperature for 3 hours, and the mixture was stirred for 1 hour. After the reaction solution was concentrated, ethyl acetate (300 ml) was added and insolubles were filtrated. The filtrate was washed with 10% aqueous citric acid, a saturated brine and dried over magnesium sulfate and an oily substance was obtained after vacuum concentration. Concentrated hydrochloric acid (200 ml) was added to an ethanol (200 ml) solution of the obtained oily substance and heated at reflux for 6 hours. After concentrated to driness under reduced pressure, the residue was washed with a mixed solvent of ethanol-isopropyl ether (1:3), collected by filtration, dried in vacuo and the title compound (25.40 g, 50%) was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: CO
Product: CC(=O)CC(=O)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 25.30 g (0.25 mol) 4-hydroxy-piperidin in 50 ml MeOH was added dropwise to a solution of 20.00 g (0.24) diketene in 50 ml MeOH at 0° C. After stirring for 1 hour at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was purified by means of column chromatography. 42.54 g (96% yield) of a slightly yellow oil was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[N:10]([CH:12]([C:14](=[O:38])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:32](=[O:37])[NH:33][CH:34]([CH3:36])[CH3:35])[CH2:29][CH:30]([OH:31])[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([N:47]=[C:48]=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[NH4+].[OH-]>C(#N)C.CO>[CH2:1]([O:8][C:9](=[O:39])[N:10]([CH:12]([C:14](=[O:38])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:32](=[O:37])[NH:33][CH:34]([CH3:35])[CH3:36])[CH2:29][CH:30]([O:31][C:48](=[O:49])[NH:47][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:24]12)=[O:22])[C:17]([CH3:18])([CH3:19])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)NC(=O)N1CC(O)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CC(C)NC(=O)N1CC(OC(=O)NCc2ccccc2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.2 %

Procedure:
A solution containing 57 (280 mg, 0.51 mmol) and benzyl isocyanate (350 μL, 2.83 mmol) in acetonitrile (500 μL) was warmed to reflux. After 12 h, the reaction mixture was cooled to ambient temperature, diluted with MeOH, and treated with aqueous NH4OH (30%, 5 mL). The solution was concentrated in vacuo and the residue was dissolved in EtOAc, washed successively with 1N HCl, water, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (2″ Dynamax® C18, 50-100% MeOH/water containing 0.1% HOAc over 20 min; Flow: 40 mL/min). The pure fractions were combined and concentrated to afford 58 as a white solid (250 mg, 72%). Mass spectrum, m/z [679.3] (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccccc2[N+](=O)[O-])C1
Yield: 85 %

Procedure:
The method of Example 1 was followed using 1-fluoro-2-nitrobenzene (1.0 eq), 3-N-Boc-aminopiperidine (1.0 eq), and DIEA (2.0 eq) in EtOH at 50° C. for 48 hours yielding tert-butyl 1-(2-nitrophenyl)piperidin-3-ylcarbamate (85%). LCMS (m/z): 322.2 (MH+); LC Rt=3.23 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([I:10])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26](Cl)=[O:27].O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:9])[C:26](=[O:27])[C:25]2[CH:24]=[C:23]([C:22]([F:37])([F:36])[F:21])[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=2)=[C:4]([I:10])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1I
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (6-chloro-4-iodo-pyridin-3-yl)-methyl-amine (300 mg, 1.12 mmol, prepared according to WO2006013050) in THF (3 mL) was added dropwise at −78° C. lithium bis(trimethylsilyl)amide (1M solution in THF, 1.17 mL, 1.17 mmol). The reaction mixture was stirred at −78° C. for 30 minutes. Then, 3,5-bis(trifluoromethyl)benzoyl chloride (340 mg, 1.23 mmol, CAS RN 1271-19-8) was added at −78° C. and the reaction was stirred for 30 minutes at this temperature. The reaction mixture was allowed to warm to room temperature, stirred for another 1 hour and then poured on 30 mL H2O and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The combined organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). Colorless solid (328 mg, 57.7%). MS (TurboSpray): m/z=508.0 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[O:22][C:16]3=[CH:17][N:18]=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=4)[CH:20]=[C:15]3[CH2:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid isopropyl ester and 4-(methanesulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.26 min; Mass spectrum (ESI+): m/z=445 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[O:25]([C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[CH:37][C:38](O)=[O:39])=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:25]([C:32]1[CH:33]=[CH:34][C:35]([CH:36]=[CH:37][C:38]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:39])=[CH:41][CH:42]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Yield: 94.4 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-phenoxycinnamic acid (3.4 g), WSC.HCl (2.7 g, 14.1 mmol), and methylene chloride (80 mL), to give the captioned compound (4.9 g, 94%) as an oily product.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@H:38]([C:52]4[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:69]([C@:76](N)([C:82]([O:84][CH:85]([C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)=[O:83])[CH2:77][O:78][C:79](Cl)=[O:80])([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70].[N:99]1C=CC=CC=1>O1CCCC1>[C:12]1([CH:18]([O:25][C:26]([C:28]2[N:33]3[C:34](=[O:60])[C@@H:35]([NH:36][C:37](=[O:59])[C@H:38]([C:52]4[CH:53]=[CH:54][C:55]([N:58]([NH2:99])[C:79]([O:78][CH2:77][C@@H:76]([C:69]([O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:70])[C:82]([O:84][CH:85]([C:86]5[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=5)[C:92]5[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=5)=[O:83])=[O:80])=[CH:56][CH:57]=4)[NH:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[C:44](=[O:50])[C:43]4=[O:51])=[O:41])[C@H:32]3[S:31][CH2:30][C:29]=2[CH2:61][S:62][C:63]2[N:67]([CH3:68])[N:66]=[N:65][N:64]=2)=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O
Reactant: CC(C)(C)OC(=O)[C@@](N)(COC(=O)Cl)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2ccc(N(N)C(=O)OC[C@H](C(=O)OC(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)C)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 12, 1.61 g of 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-[(2S)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate are reacted with 1.33 g of (2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonyl chloride and 0.34 ml of pyridine in 40 ml of tetrahydrofuran and worked up. The resulting crude product is chromatographed over 250 g of silica gel and 250 ml fractions are taken. The fractions are eluted with toluene/ethyl acetate (1:1). By reprecipitating fractions 16-37 from CH2Cl2 /ether/hexane, 3-[(1-methyl-1H-tetrazol-5-yl)-thiomethyl]-7β-{(2S)-2-[4-((2R)-2-BOC-amino-2-diphenylmethoxycarbonylethoxycarbonylamino)-phenyl]-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido}-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained. IR: 3405, 3302, 1782, 1715 (wide), 1690 (shoulder), 1610, 1595, 1510 cm-1 (CH2Cl2).
Reaction SMILES: O.O.O.O.O.O.O.O.O(Cl)Cl.[Zr:12].O.O.C(O)(=O)C(O)=O.[P:21](=[O:25])([OH:24])([OH:23])[OH:22]>O>[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[Zr+4:12].[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[P:21]([O-:25])([O-:24])([O-:23])=[O:22].[Zr+4:12].[Zr+4:12]
Reactant: O=P(O)(O)O
Reactant: [Zr]
Agent: ClOCl
Agent: O=C(O)C(=O)O
Solvent: O
Product: O=P([O-])([O-])[O-]
Product: [Zr+4]

Procedure:
0.272 mol of zirconium oxychloride octahydrate was dissolved in 850 ml of deionized water, and thereafter, 0.788 mol of oxalic acid dihydrate was dissolved therein. 0.57 mol of phosphoric acid was added to the solution under stirring. The solution was stirred and refluxed for 8 hours. After cooling, the obtained precipitate was well washed with water, and thereafter dried at 105° C. to obtain a zirconium phosphate. As a result of measurement of the obtained zirconium phosphate, it was confirmed to be a layered zirconium phosphate.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:8][C:9]([CH3:29])=[CH:10][CH2:11][CH2:12]/[C:13](/[CH3:28])=[CH:14]/[CH2:15][CH2:16]/[C:17](/[CH3:27])=[CH:18]/[CH2:19][S:20][CH2:21][C@H:22]([NH2:26])[C:23]([OH:25])=[O:24].C(N(CC)C(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[CH:1]1([S:4]([NH:26][C@@H:22]([CH2:21][S:20][CH2:19]/[CH:18]=[C:17](\[CH3:27])/[CH2:16][CH2:15]/[CH:14]=[C:13](\[CH3:28])/[CH2:12][CH2:11][CH:10]=[C:9]([CH3:29])[CH3:8])[C:23]([OH:25])=[O:24])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=S(=O)(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NS(=O)(=O)C1CC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, to a suspension of cyclopropanesulfonyl chloride (169 mg, 1.2 mmol) and S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) in THF (5 mL) was added N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol) dropwise. The solution was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (60 mL) and washed by 0.5 N HCl (10 mL×1), H2O (10 mL×2) and brine (10 mL×1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was then further purified by preparative HPLC (50 mg, 12%) to yield Compound N-79. 1H-NMR (500 MHz, CD3OD): δ 0.86-0.89 (m, 2H), 0.93-0.96 (m, 2H), 1.50 (s, 3H), 1.51 (s, 3H), 1.57 (s, 3H), 1.61 (s, 3H), 1.86-1.89 (m, 2H), 1.95-1.98 (m, 4H), 2.00-2.04 (m, 2H), 2.43-2.46 (m, 1H), 2.66-2.68 (m, 1H), 2.76-2.79 (m, 1H), 3.09-3.13 (m, 1H), 3.16-3.21 (m, 1H), 4.02 (t, J=5.0 Hz, 1H), 4.99-5.01 (m, 2H), 5.15 (t, J=5.0 Hz, 1H). 13C-NMR (125 MHz, CD3OD): δ 5.58, 6.28, 16.16, 16.30, 17.81, 25.96, 27.39, 27.80, 30.41, 31.73, 34.88, 40.79, 40.90, 57.75, 121.67, 125.17, 125.47, 132.12, 136.28, 140.55, 174.39; ES-MS: mass calcd for Chemical Formula: C21H35NO4S2 429.64. Found (M+) m/z 430.2, (M+Na) m/z 452.2.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1C1SC=C(C(O)=O)N=1.[F:19][C:20]1[CH:21]=[C:22]([C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)[CH:23]=[C:24]([F:35])[C:25]=1B1OC(C)(C)C(C)(C)O1.Br[C:42]1[N:47]=[C:46]([C:48]([O:50]C)=[O:49])[CH:45]=[CH:44][C:43]=1[F:52]>>[F:35][C:24]1[CH:23]=[C:22]([C:36]2([OH:40])[CH2:37][CH2:38][CH2:39]2)[CH:21]=[C:20]([F:19])[C:25]=1[C:42]1[N:47]=[C:46]([C:48]([OH:50])=[O:49])[CH:45]=[CH:44][C:43]=1[F:52]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Agent: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CCC3)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (Intermediate 108) and replacing methyl 2-bromothiazole-4-carboxylate with methyl 6-bromo-5-fluoropicolinate (see US2012/225062) gave the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:45])[N:13]([C:16]1[C:20]2[CH:21]=[N:22][C:23](Cl)=[CH:24][C:19]=2[N:18]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:17]=1)[CH2:14][CH3:15])([CH3:10])([CH3:9])[CH3:8].[C:46](=[O:56])([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[NH2:47].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1>[C:7]([O:11][C:12](=[O:45])[N:13]([C:16]1[C:20]2[CH:21]=[N:22][C:23]([NH:47][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:56])=[CH:24][C:19]=2[N:18]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:17]=1)[CH2:14][CH3:15])([CH3:10])([CH3:9])[CH3:8]
Reactant: NC(=O)OCc1ccccc1
Reactant: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN(C(=O)OC(C)(C)C)c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ncc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A 20 mL microwave vial was charged with cesium carbonate (907 mg, 2.78 mmol), tert-butyl(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)(ethyl)carbamate (500 mg, 0.928 mmol), benzyl carbamate (421 mg, 2.78 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (34.9 mg, 0.065 mmol) and BrettPhos-G3-Pd (58.9 mg, 0.065 mmol). Dioxane (10 ml) was added, the vial was flushed with argon, capped and the contents heated to 100° C. with stirring for 16 h. The reaction mixture was diluted with DCM/i-PrOH (4:1, 50 mL) and washed with brine (2×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (ISCO; 24 g prepacked) eluting with ethyl acetate/hexanes to afford tert-butyl(6-(((benzyloxy)carbonyl)amino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)(ethyl)carbamate (225 mg, 0.344 mmol, 37.1% yield) as a white solid. MS ESI calc'd. For C40H40N5O4 [M+H]+ 654. found 654.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (3.5 g), 1-BOC-piperazine (2.76 g) and trimethylorthoformate (4.05 mL) was stirred in 1,2-dichloroethane (300 mL) for 1 hr at room temperature. To this was added sodium triacetoxyborohydride (3.92 g) and the reaction mixture was stirred for 24 hours at room temperature. The mixture was then quenched with brine, extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (3.4 g). Treatment with HCl in dichloromethane/methanol yielded 4-(2-chloro-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine 30.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([CH3:3])=[CH2:2]>O1CCCC1.[OH-].[OH-].[Pd+2]>[CH:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cnc2[nH]ccc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cnc2[nH]ccc2c1
Reaction time: 0.5 h

Procedure:
To 5-isopropenyl-1H-pyrrolo[2,3-b]pyridine (12, 0.080 g, 0.501 mmol) in tetrahydrofuran (5.0 mL) was added 20% palladium hydroxide on carbon (5.0 mg). The reaction was stirred under hydrogen at 40 psi for 30 minutes. The reaction mixture was filtered and concentrated to give the compound (13, 0.078 g, 96%). MS (ESI)[M+H+]+=161.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([C:17](=[O:37])[NH:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:35])([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])=[CH:21][C:20]=2[Cl:36])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([C:17]([NH:18][C:19]2[C:20]([Cl:36])=[CH:21][C:22]([C:26]([F:35])([C:27]([F:28])([F:29])[F:30])[C:31]([F:32])([F:34])[F:33])=[CH:23][C:24]=2[Cl:25])=[O:37])=[CH:16][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
Tert-butyl (2-chloro-4-{[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-phenyl]carbamoyl}benzyl)carbamate (0.85 g) was dissolved in methylene chloride (15 ml). Trifluoroacetic acid (2 ml) was added to the solution, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (15 ml), and an aqueous solution of potassium carbonate was added to the solution under stirring. The organic phase was separated and the aqueous layer was extracted with methylene chloride and dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product (0.65 g) of 4-(aminomethyl)-3-chloro-N-[2,6-dichloro-4-(1,1,1,2,3,3,3heptafluoro propan-2-yl)-phenyl]benzamide. The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:23])([F:22])[F:21])=[N:15][C:16]([C:17]([OH:19])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:26][NH2:27].C(N(CC)CC)C.[O:35]=[C:36]1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:20]([F:21])([F:23])[F:22])=[N:15][C:16]([C:17](=[O:19])[N:27]([O:35][CH3:36])[CH3:26])=[C:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: COCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Yield: 100.9 %

Procedure:
3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-tert-butyl ester 27d (1.84 g, 5.5 mmol) and N-methoxy methyl-amine (0.805 g, 8.25 mmol) were dissolved in 50 mL of dichloromethane under stirring, and triethylamine (3 mL, 22 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.1 g, 8.25 mmol) were then added to the solution. The reaction mixture was reacted overnight at room temperature and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (2.1 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([NH2:13])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14](Br)[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CC(C)=O>[CH2:14]([O:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([NH2:13])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: NC(=O)c1cc2c(O)cccc2o1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOc1cccc2oc(C(N)=O)cc12
Temperature: 0 °C
Yield: 99.4 %

Procedure:
A mixture of 1 g (5.64 mmol) of 4-hydroxybenzofuran-2-carboxamide, 0.5 ml (6.77 mmol) of ethyl bromide, 1.56 g (11.3 mmol) of potassium carbonate, 6 ml of anhydrous DMF and 50 ml of anhydrous acetone was heated at reflux over 24 hours. Subsequently, the mixture was poured on to 70 ml of ice-water, extracted twice with 100 ml of ethyl acetate each time and the combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. There were obtained 1.15 g (99%) of 4-ethoxybenzofuran-2-carboxamide as a yellow solid with m.p. 113°.