Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[N:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[CH2:28]([O:31][C:32]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][CH3:47])[CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35])[CH2:29][CH3:30]>C1COCC1>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:34]([C:33]2[CH:40]=[CH:41][C:42]([O:44][CH2:45][CH2:46][CH3:47])=[CH:43][C:32]=2[O:31][CH2:28][CH2:29][CH3:30])=[O:35])=[CH:23][CH:22]=1
Reactant: Cc1ccncc1
Reactant: CCCOc1ccc(C(=O)N(C)OC)c(OCCC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCOc1ccc(C(=O)Cc2ccncc2)c(OCCC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a cooled solution of lithium diisopropylamide (generated from diisopropylamine (109 mg, 1.07 mmol) and a solution of n-butyllithium in hexanes (0.49 mL of a 2.5M solution, 1.22 mmol)) in THF (0.5 mL) at -78° C. was added 4-picoline (95 μL, 0.98 mmol). Stirred -78° to 0° C. for 1 h. The reaction mixture was cooled to -78° C. and a solution of 2,4-di-n-propyloxy-N-methoxy-N-methyl-benzamide from Step B (274 mg, 0.98 mmol) in THF (0.5 mL) was added dropwise. The reaction was stirred <0° C. for 4 h and then quenched by the addition of a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate (2 times). The combined extracts were successively washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The solution was filtered and the solvents removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 0-50% ethyl acetate in hexanes to yield the title compound (147 mg, 48% yield), mass spectrum (CI) m/e=314 (M+1)+.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[CH3:45][N:46]1[CH:50]=[CH:49][N:48]=[C:47]1[Sn](CCCC)(CCCC)CCCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([C:47]2[N:46]([CH3:45])[CH:50]=[CH:49][N:48]=2)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccccc3)c(Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(-c3nccn3C)c(Cc3ccccc3)c(Cl)c2c1
Temperature: 110 °C

Procedure:
A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1.01 g, 1.86 mmol, Example 109), 1-methyl-2-(tributylstannyl)-1H-imidazole (1.42 g, 3.68 mmol), Pd(PPh3)4 (206 mg, 0.180 mmol), and toluene (10 mL) was sparged with N2 for about 10 minutes, then heated at 83° C. for 16 hours and 110° C. for 3 hours. After cooling down to room temperature, the mixture was concentrated in vacuo and DCM was added. The precipitated solid was filtered and dissolved in DMSO and MeOH. A few drops of TFA were added to improve solubility. The mixture was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 9.06 (s, 1H), 8.94 (s, 1H), 8.86 (d, J=2.02 Hz, 1H), 8.54 (d, J=2.02 Hz, 1H), 8.22 (d, J=9.09 Hz, 1H), 8.16 (dd, J=2.02, 8.08 Hz, 1H), 7.90-7.94 (m, 2H), 7.64 (d, J=1.52 Hz, 1H), 7.19-7.26 (m, 3H), 7.18 (d, J=1.52 Hz, 1H), 6.86-6.90 (m, 2H), 4.54 (s, 2H), 3.74 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C([O-])(O)=[O:16].[Na+].CS([O-])(=O)=O.[CH3:25][N+:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28](OC)[CH:27]=1>P([O-])([O-])([O-])=O>[OH2:11].[OH2:16].[CH3:8][C:6]1([CH3:9])[CH:5]([C:10]([OH:12])=[O:11])[N:4]2[C:13](=[O:14])[CH:2]([NH:1][C:27]3[N:26]([CH3:25])[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=3)[C@H:3]2[S:7]1
Reactant: O=C([O-])O
Reactant: COn1c[n+](C)c2ccccc21
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)O
Agent: CS(=O)(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: Cn1c(NC2C(=O)N3C(C(=O)O)C(C)(C)S[C@H]23)nc2ccccc21
Product: O
Reaction time: 6 h

Procedure:
6-Amino-2,2-dimethylpenam-3-carboxylic acid (324 mg.) was dissolved in phosphate buffer at pH 7 using one equivalent of NaHCO3. To the stirred solution was added 1-methyl-3-methoxybenzimidazolium methane-sulphonate and stirring was continued for 6 hours at ambient temperature. The white solid which precipitated was filtered, washed with ice-cold water and dried in vacuo over P2O5 to give 2,2-dimethyl-6-(1-methylbenzimidazol-2-yl)aminopenam-3-carboxylic acid dihydrate (186 mg.) having the following n.m.r in d6DMSO: 1.5 (s, 3H); 1.65 (s, 3H); 3.6 (s, 3H); 4.25 (s, 1H); 5.55 (m, 2H); 6.9-7.4 (m, 4H).
Reaction SMILES: Cl.[CH:2]1([O:6][C:7]2[CH:8]=[C:9]([F:15])[C:10]([F:14])=[C:11]([NH2:13])[CH:12]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[C:17]1(Cl)[C:23](=O)C([Cl:25])=C(Cl)[C:19](=O)[C:18]=1Cl.C(=O)/C=C/C>C(O)CCC.O1CCCC1>[ClH:25].[CH:2]1([O:6][C:7]2[CH:8]=[C:9]([F:15])[C:10]([F:14])=[C:11]3[C:12]=2[CH:23]=[CH:17][C:18]([CH3:19])=[N:13]3)[CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cc(OC2CCC2)cc(F)c1F
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: C/C=C/C=O
Agent: Cl
Solvent: CCCCO
Solvent: C1CCOC1
Product: Cc1ccc2c(OC3CCC3)cc(F)c(F)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 5-cyclobutoxy-2,3-difluorobenzenamine hydrogen chloride (9.9 g, 42.1 mmol), concentrated hydrochloric acid (36 mL), chloranil (12.32 g, 49.8 mmol) in n-butanol (60 mL) stirred for 1 h at 100° C. (E)-Crotonaldehyde (19.8 mL, 239 mmol) was added dropwise, and the resulting solution stirred for 1 h at 100° C. and was then cooled to 70° C. Tetrahydrofuran (600 mL) was added, and the mixture stirred for another 30 min at 70° C. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was poured into water (300 mL) and the pH of the mixture was adjusted to 7-8 with saturated aqueous potassium carbonate solution. The resulting mixture was extracted with ethyl acetate (3×300 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate/petroleum ether) to afford 5-cyclobutoxy-7,8-difluoro-2-methylquinoline hydrochloride (6 g, 57%) as a yellow solid. MS (ESI, pos. ion) m/z 250 [M+H]+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)([O:13][CH2:14][CH3:15])=[O:12].CN1C[CH2:32][CH2:31]N(C)C1=O.BrCCCl>O1CCCC1>[C:11]([C:16]1([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:32][CH2:31]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CN1CCCN(C)C1=O
Reactant: CCOC(=O)CSCc1ccc(OC)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: ClCCBr
Solvent: C1CCOC1
Product: CCOC(=O)C1(SCc2ccc(OC)cc2)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
Cool lithium hexamethyldisilazane (6 mL of a 1.0M solution tetrahydrofuran, 6.0 mmol) to -78° C. Add, by cannula transfer, a solution of 1-(carboethoxy)-1-(4-methoxybenzylthio)methane (1.36 g, 5.66 mmol) in tetrahydrofuran (10 mL). Stir for 45 minutes, add 1,3-dimethyl -3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (0.73 mL, 6.0 mmol) followed by 1-bromo-2-chloroethane (050 mL, 6.0 mmol) and stir to room temperature overnight. Cool to -78° C., add lithium hexamethyldisilazane (6.0 mL, 6.0 mmol) and stir at room temperature for 24 hours. Quench with saturated ammonium chloride (5 mL) and partition between ethyl acetate (30 mL) and water (30 mL). Separate the organic phase, dry (Na2SO4) and evaporate the solvent in vacuo. Purify by chromatography (5:1 hexane/ethyl acetate to 2.5:1 hexane/ethyl acetate) to give 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclopropane (317 mg, 21%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]2=[O:16])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.I[CH3:18]>>[F:1][C:2]1[C:3]([N:9]2[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([CH3:18])[C:10]2=[O:16])=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: CC1(C)CN(c2ncc(I)cc2F)C(=O)N1
Reactant: CI
Product: CN1C(=O)N(c2ncc(I)cc2F)CC1(C)C

Procedure:
The title compound, a yellow oil, MS: m/e=350.0 (M+H+), was prepared in accordance with the general method of Example 16 from 1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 110, step 1) and iodomethane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20](I)=[CH:21][C:16]=2[C:15](=[O:23])[N:14]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:25])[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:12]1=[O:40])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:49][OH:50].CN([CH:54]=[O:55])C>>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:49]([O:55][CH3:54])=[O:50])=[CH:21][C:16]=2[C:15](=[O:23])[N:14]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:25])[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:12]1=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CO
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2N(CCCCC(=O)OC(C)(C)C)C(=O)[C@@H]1c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 5-[(3S)-3-(4-chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-2,5-dioxo-3,4-dihydro-1H-1,4-benzodiazepin-1-yl]valeric acid tert-butyl ester (300 mg, 0.42 mmol), dichloro bis-(triphenylphosphine)Pd(II) (21 mg, 0.030 mmol), and triethylamine (200 μL, 1.43 mmol), in DMF (4 mL) and methanol (1.5 mL) was stirred under a carbon monoxide atmosphere at 80° C. for 24 h. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure. The crude reaction product was purified by column chromatography on silica gel (EtOAc/hexanes, 1:2) to give the title compound (226 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H, 3 CH3), 1.58–1.62 (m, 2H, CH2), 1.75 (d, J=5.4 Hz, 3H, CH3), 2.24 (t, J=10.5 Hz, 2H, CH2), 3.62–3.90 (m, 3H, 3 CH), 3.91 (s, 3H, CH3), 4.23–4.31 (m, 1H, CH), 5.34 (s, 1H, CH), 6.45 (q, J=5.4 Hz, 1H, CH), 6.50 (d, J=6.3 Hz, 2H, ArH), 6.84 (d, J=6.3 Hz, 2H, ArH), 6.94 (d, J=6.6 Hz, 1H, ArH), 7.32 (d, J=6.6 Hz, 2H, ArH), 7.50 (d, J=6.3 Hz, 2H, ArH), 7.84 (dd, J=6.3 Hz, J=1.5 Hz, 1H, ArH), 8.33 (d, J=1.5 Hz, 1H, ArH).
Reaction SMILES: [CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.CN([CH:29]=[O:30])C.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:1]([C:11]1[S:15][C:14]([C:16]2[S:17][C:18]([CH:29]=[O:30])=[CH:19][CH:20]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCc1ccc(-c2cccs2)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCc1ccc(-c2ccc(C=O)s2)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
5-Decyl-2,2′-bithiophene (39.0 g, 0.127 mol) prepared above and THF (300 ml) were placed in a 1000-ml three-necked flask equipped with a 200-ml dropping funnel and a reflux tube. The solution was cooled in an ice bath to 0° C., and a solution (80 ml) of n-butyllithium (1.6 M) in n-hexane was added dropwise to the cooled solution over a period of about one hr. After the completion of the dropwise addition, the mixture was stirred for about one hr. DMF (13.9 g, 0.191 mol) was added dropwise thereto at 0° C. over a period of about one hr. After the completion of the dropwise addition, the reaction temperature was raised to room temperature, and, at that temperature, the mixture was stirred overnight. After the completion of the reaction, a 1 N ammonium chloride solution (200 ml) was added, and the organic layer was extracted with diethyl ether, was dried over sodium sulfate, and was applied to column chromatography (CH2Cl2:hexane=1:1) to give an objective compound 5-decyl-5′-formyl-2,2′-bithiophene as a yellow solid (37.2 g, yield 87.60%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 14H), 1.69 (m, 2H), 2.81 (t, 2H, J=7.32 Hz), 6.74 (d, 1H, J=3.90 Hz), 7.16 (d, 1H, J=3.90 Hz), 7.18 (d, 1H, J=3.90 Hz), 7.64 (d, 1H, J=3.90 Hz), 9.84 (s, 1H).
Reaction SMILES: [CH3:1][SH:2].[Na].F[C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C(O)C.Cl>O>[CH3:1][S:2][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CS
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reaction time: 48 h

Procedure:
2.5 mL of 15% sodium methylmercaptan aqueous solution was added to the mixture of 11.0 g (5.40 mmol) of 5-fluoro-2-nitrobenzoic acid and 5 mL of ethanol and stirred for 2 days. Then, 10 mL of water was added and pH thereof was adjusted to become 1 by concentrated hydrochloric acid. After filtering out the precipitated compound, it was washed with water, ether and hexane and dried to obtain a crude material of 5-methylthio-2-nitrobenzoic acid. 3 mL of thionyl chloride was added to the obtained crude material and stirred for 5 hours. The thionyl chloride was removed to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH2:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[S:45][CH:46]([C:50](O)=[O:51])[C:47](O)=[O:48])[CH:36]([CH3:38])[CH3:37]>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:47](=[O:48])[C:46]([S:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[CH2:35][CH:36]([CH3:37])[CH3:38])=[C:50]([OH:51])[CH:14]=2)[CH:8]=1
Reactant: CC(C)Cc1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Cc1ccccc1Sc1c(O)cc(-c2cccc(-c3ccccc3)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3'-phenylacetophenone (2 g, 10.20 mmol), trimethylsilyl triflate (2.27 g, 10.20 mmol), triethylamine (2.06 g, 20.40 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isobutylphenyl)thio]propanedioic acid (1.14 g, 5.1 mmol). m.p. 187-188° C. 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, 6H), 1.78 (m, 1H), 2.4 (d, 2H), 7.03 (s, 1H), 7.08 (s, 4H), 7.44 (t, 1H), 7.53 (t, 2H), 7.67 (t, 1H), 7.75 (s, 1H), 7.78 (s, 1H), 7.86 (m, 2H), 8.08 (s, 1H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][C@H:14]([NH:18]C(OC(C)(C)C)=O)[C:15]([OH:17])=O)=O)C1C=CC=CC=1.[CH3:26][S:27]([Cl:30])(=[O:29])=[O:28].[S:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>>[ClH:30].[NH2:18][C@H:14]([C:15](=[O:17])[N:33]1[CH2:34][CH2:35][S:31][CH2:32]1)[CH2:13][CH2:12][NH:11][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)O
Product: CS(=O)(=O)NCC[C@H](N)C(=O)N1CCSC1
Product: Cl

Procedure:
Starting from (S)-4-[(benzyloxycarbonyl)-amino]-2-[(tert-butyloxycarbonyl)-amino]-butanoic acid, methanesulphonyl chloride and 1,3-thiazolidine, the expected product is obtained according to the procedure described in Example 3.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:25][S:26]([N:29]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30]1)(=[O:28])=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][S:26]([N:29]1[CH2:33][CH2:32][CH:31]([NH:34][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[CH:11]=2)=[O:15])[CH2:30]1)(=[O:28])=[O:27]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: CS(=O)(=O)N1CCC(N)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
In a round-bottomed flask were combined 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (130 mg, 0.39 mmol), 1-methanesulfonyl-pyrrolidin-3-ylamine hydrochloride (134 mg, 0.66 mmol), EDC (82 mg, 0.43 mmol), and HOBt (58 mg, 0.43 mmol). Then added DMF (1.7 mL) followed by i-Pr2NEt (0.17 mL, 1.0 mmol). The reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with Et2O (2×). The combined organics were washed with H2O (2×) and brine then dried over Na2SO4 and concentrated. The residue was purified by chromatography over 12 g of SiO2 using EtOAc/hexanes (gradient: 0-90% EtOAc) to afford 179 mg (96%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-yl)-amide as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[C:45]3[CH:46]=[CH:47][S:48][C:44]=3[CH2:43][CH2:42][NH:41]2)=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([CH:40]2[C:45]3[CH:46]=[CH:47][S:48][C:44]=3[CH2:43][CH2:42][N:41]2[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[O:8])=[CH:38][CH:39]=1
Reactant: Clc1ccc(C2NCCc3sccc32)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)N1CCc2sccc2C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Hydroxybenzoic acid (1.3 g, 9.6 mmol) was dissolved in N,N-dimethylformamide (25 ml) and 1-hydroxybenzotriazole (1.3 g, 9.6 mmol) was added followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.8 g, 9.6 mmol), 4-(4-chlorophenyl)4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (2.0 g, 8 mmol) and N,N-diisopropylethylamine (2.5 ml, 16 mmol). The resulting mixture was stirred at room temperature for 16 hours. Water (200 ml) was added and the mixture was extracted with diethyl ether (3×100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (150 ml), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography over silica gel eluting with a mixture of ethyl acetate and heptane (1:1). The pure fractions were pooled and concentrated in vacuo to afford 3.14 9 (100%) of the title compound.
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].CP(=O)(OCC)OCC.B(F)(F)F.C[CH2:20][O:21][CH2:22][CH3:23].[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:28]([O:24][CH2:23][C@H:22]1[CH2:20][O:21]1)[C:27]1[CH:4]=[CH:3][CH:2]=[CH:25][CH:26]=1
Reactant: [Li]CCCC
Reactant: CCOCC
Reactant: C1CCOC1
Agent: CCOP(C)(=O)OCC
Agent: FB(F)F
Product: c1ccc(COC[C@H]2CO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (2.5M in hexane, 72 mL, 180 mmol) was added dropwise to a solution of diethyl methylphosphonate (27.4 g, 180 mmol) in 200 mL dry tetrahydrofuran (THF) at -78° C. After 30 minutes of stirring at -78° C., the resulting white suspension was added in a slow stream through a cannula to a stirred solution of BF3.Et2O (22.13 mL, 180 mmol) in THF (400 mL) at -78° C. After 10 minutes, neat (R)-(-)-2-(benzyloxymethyl)oxirane 1-1 (10 g, 61 mmol, obtained from the Aldrich Chemical Co.) was added quickly to this suspension. The reaction mixture was stirred for 30 minutes at -78° C., quenched by adding saturated aqueous NaHCO3 (100 mL) and allowed to warm to room temperature. The reaction was diluted with 450 mL of ether and washed with 2×200 mL of saturated sodium bicarbonate solution and 100 mL of brine. The ether layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with 5% methanol/95% dichloromethane to give the product 1-2 as a pale yellow oil (18.0 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:39][C:40]([F:48])([F:47])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([N:44]5[CH2:45][CH2:46][CH:41]([C:40]([F:48])([F:47])[F:39])[CH2:42][CH2:43]5)=[O:34])=[CH:31][CH:32]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Yield: 81.4 %

Procedure:
Stir a solution of 4-[(R)-3-(4′-Carboxy-3,5-dichloro-biphenyl-4-ylmethyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 25) (0.1 g, 0.18 mmol), 4-(Trifluoromethyl)piperidine Hydrochloride (42 mg, 0.22 mmol), N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol), 1-Hydroxybenzotriazole (73 mg, 0.22 mmol) and 4-Methylmorpholine (0.08 mL, 0.73 mmol) in CH2Cl2 (3 mL) at room temperature for 6 hr. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.10 g (80%) of desired product. MS (m/e): 582 (M−BOC+).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Sn](CCCC)(CCCC)CCCC>>[ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:31]5[O:30][CH:34]=[CH:33][CH:32]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccco6)ccc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochloride and (furan-2-yl)-tri-n-butylstannane; δH [2H6] DMSO 9.94(1H,bs), 8.61(1H,d), 8.55(1H,s), 8.21(2H,d), 8.00(3H,m), 7.73(2H,s), 7.30(6H,s), 6.74(1H,s), 5.72(2H,s); m/z (M+1+) 418.