Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1.COC(OC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[S:28])[CH:11]([O:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)C(OC)C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: COC(C)OC
Product: COC(=O)C(OC)C(=S)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 116.7 %

Procedure:
A mixture of 3.50 grams (0.01 mole) of methyl 3-[(3,5-dichlorophenyl)amino]-2-methoxy-3-oxopropanoate (Compound 233, Example LXX), 2.42 grams (0.006 mole) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide and 35 milliliters of anhydrous 1,1-dimethoxyethane was stirred at room temperature for a period of about 20 hours after which stirring was continued with testing at 55° C. for a 168-hour interval. Solvent was removed from the reaction mixture under reduced pressure and the residue worked up by flash column chromatography to give 2.31 grams (0.007 mole) of methyl 3-[(3,5-dichloro-phenyl)amino]-2-methoxy-3-thioxopropanoate having a melting point of 144° C.-147° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>CS(C)=O>[O:21]=[C:15]1[C:14]2[CH:13]=[C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[N:3]=[C:2]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]3)[CH:11]=[CH:10]4)[NH:20][C:19]=2[CH2:18][CH2:17][NH:16]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 231.7 %

Procedure:
A solution of 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (Small Molecules, Inc., Hoboken, N.J.; 168 mg, 0.840 mmol) in DMSO (0.5 mL) was stirred under argon at 100° C. for 19 h, then 130° C. for 5 h, then 150° C. for 17 h. The mixture was cooled to 25° C. and partitioned between DCM (30 mL) and water (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were sequentially washed with water (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide crude (R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)amino)piperidine-1-carboxylate (179.7 mg) as a brown foam (used without further purification in the subsequent transformation): m/z (ESI, +ve) 462.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[O:16])=[CH:10][CH:9]=1>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:16])=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of morpholine (16 g, 183.91 mmol, 1.98 equiv) in dichloromethane (50 mL) at 0-5° C. was added a solution of 2-(4-bromophenyl)acetyl chloride (21.5 g, 92.67 mmol, 1.00 equiv) in dichloromethane (20 mL) dropwise with stirring. The reaction mixture was stirred for another hour at 0˜5° C. The reaction mixture was warmed to room temperature and diluted with 30 mL of dichloromethane. The mixture was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 19.5 g (74%) of 2-(4-bromophenyl)-1-morpholinoethanone as a white solid. LC-MS: (ES, m/z): 284 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH:38]([F:40])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][C@@H:34]4[C@@H](CN(C)C4)C3)=[O:27])[N:9]=2)[CH:7]=1.ClC1C=CC(OC(F)F)=C(C2[C:52](NC(C3C=NN4C=CC=NC=34)=O)=[CH:51][N:50]([CH2:65]C(O)=O)N=2)C=1.CN1CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:37][CH:38]([F:40])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][CH2:34][N:50]([CH3:65])[CH2:51][CH2:52]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN1C[C@@H]2CN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)C[C@@H]2C1
Agent: CN1CCNCC1
Product: CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1

Procedure:
The title compound was prepared in an analogous manner to cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide using {3-(5-chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid and methyl piperazine to afford the title compound as a pale yellow solid. LCMS (Method 5) [M+H]+=545.1, RT=2.89 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.85 (s, 1H), 8.78 (dd, 1H, J=1.6, 7.0 Hz), 8.71 (s, 1H), 8.56 (dd, 1H, J=1.7, 4.1 Hz), 8.41 (s, 1H), 7.69 (d, 1H, J=2.6 Hz), 7.41 (dd, 1H, J=2.6, 8.7 Hz), 7.28 (d, 1H, J=9.1 Hz), 7.00 (dd, 1H, J=4.2, 7.0 Hz), 6.47 (t, 1H, J=74.1 Hz), 5.04 (s, 2H), 3.72-3.65 (m, 2H), 3.57 (dd, 2H, J=4.8, 4.8 Hz), 2.47-2.39 (m, 4H), 2.31 (s, 3H).
Reaction SMILES: [I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22].C(=O)([O-])[O-].[K+].[K+].O>C(O)C.C(=O)([O-])[O-].[K+].[K+]>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:22]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: C[N+]1(Cc2ccccc2)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCC(=O)CC2)cc1OC
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A slurry of 1-benzyl-1-methyl-4-oxo-piperidinium iodide (9270 mg), 3,4-dimethoxy aniline (3900 mg) and anhydrous potassium carbonate (437 mg) in ethanol (90 ml)/water (45 ml) were heated to reflux for 6 hours. Additional potassium carbonate (200 mg) was added and the reaction was heated to 100° C. over night. Water (50 ml) was added to the reaction mixture, which was extracted three times with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and the solvent was evaporated in vacuo to leave the crude product as a dark oil. The residue was purified by column chromatography (ethyl acetate/hexanes=1:1) to yield the product as a yellow solid (3700 mg). MS (ESI): 236.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB(C2C(C3C=CC(C(OC)=O)=CC=3)=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2)O1.CC1(C)C(C)(C)OB([C:68]2[C:69]([C:92]3[CH:102]=[CH:101][C:95]([C:96]([O:98][CH2:99][CH3:100])=[O:97])=[CH:94][CH:93]=3)=[N:70][N:71]([C:73]([C:86]3[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=3)([C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[CH:72]=2)O1.N1C=CC=CC=1C1N2C=C(C3C(C4C=CC(C(OC)=O)=CC=4)=NN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3)C=CC2=NC=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([C:68]3[C:69]([C:92]4[CH:93]=[CH:94][C:95]([C:96]([O:98][CH2:99][CH3:100])=[O:97])=[CH:101][CH:102]=4)=[N:70][N:71]([C:73]([C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)([C:86]4[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=4)[C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[CH:72]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Brc1ccc2ncc(-c3ccccn3)n2c1
Reactant: CCOC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)cc1
Agent: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: COC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1

Procedure:
2 g 6-bromo-3-(2-pyridyl)imidazo[1,2-a]pyridine (compound in Production Example 63) and 5 g mixture of methyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate and ethyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate were reacted in the same manner as in Example 10, whereby 4.54 g mixture of methyl 4-[4-(3-pyridin-2-ylimidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]-benzoate and ethyl 4-[4-(3-pyridin-2-ylimidazo[1,2-a]-pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]benzoate was obtained as a pale yellow amorphous. 638 mg of this ester mixture was added to 10 mL suspension of 50 mg lithium aluminum hydride in tetrahydrofuran, and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled on iced water, then 220 mg sodium fluoride and 80 μL water were added thereto, and the reaction solution was returned to room temperature and stirred for 40 minutes. Insolubles were filtered off, and the filtrate was evaporated. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 298 mg of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2.I[CH3:24]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:22])[N:14]([CH3:24])[C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[CH:17][CH:16]=2
Reactant: CI
Reactant: O=c1[nH]c2ccncc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2cnccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 3-(2,6-dichloro-3-nitro-phenyl)-1H-[1,6]naphthyridin-2-one (2.0 g, 5.95 mmol) in DMF (50 mL) is added HNa (286 mg, 60%, 7.14 mmol) and IMe (0.5 mL, 8.03 mmol) at 0° C. The mixture is stirred for two hours at 0° C., diluted with EtOAc (300 ml) and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give crude product, which is purified by flash silica gel column elute with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3)(98.5/1.5) to give the titled intermediate as a solid (1.67 g, 80.3%).
Reaction SMILES: [CH3:1][O-].[K+].[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][C:15]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=3[NH:13][C:12](=[O:22])[C:11]=2[CH:23]=1)([O-:6])=[O:5].IC>C(O)(C)(C)C.O1CCOCC1>[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][C:15]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=3[N:13]([CH3:1])[C:12](=[O:22])[C:11]=2[CH:23]=1)([O-:6])=[O:5]
Reactant: Cc1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1C(=O)N2
Reactant: C[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)Oc1ccc([N+](=O)[O-])cc1C(=O)N2C
Temperature: 60 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a warm solution of 4.05 g potassium methoxide in 80 ml of t-butanol and 80 ml of dioxane was added 13.5 g (0.05 mol) of 2-nitro-7-methyldibenz[b,f][1,4]oxazepin-11(10H)-one. The resulting suspension was warmed to 60° C. for 15 minutes. Initially everthing went in solution, after several minutes a crystalline precipitate formed. To the stirred suspension was added 3.75 ml of iodomethane. The reaction mixture was stirred for 4 hours at 60° C., then concentrated to dryness in vacuo. The dark residue was suspended in water, acidified with acetic acid, concentrated in vacuo and then recrystallized from propanol to give 8.5 g (60% yield) of 2-nitro-7,10-dimethyldibenz[b,f][1,4]- oxazepin-11(10H)-one mp 156°-159°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:20]([CH3:22])([CH3:21])[O:19][C:18]([NH:23][C@H:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[N:17][S:16]2(=[O:42])=[O:41])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(CC)CC)C>CO.[Pd]>[OH:27][CH2:26][CH2:25][C@H:24]([NH:23][C:18]1[O:19][C:20]([CH3:22])([CH3:21])[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[S:16](=[O:41])(=[O:42])[N:17]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1ccc(O)cc1
Reaction time: 1 h
Yield: 20.5 %

Procedure:
Under inert gas, 762 mg [5-(4-benzyloxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropyl]amine were initially charged in 20 ml of methanol and, with addition of 133 mg of 10% Pd/C, stirred under a hydrogen atmosphere for 1 hour. The completeness of the conversion was checked by LCMS, the reaction was once again admixed with 133 mg of 10% Pd/C and additionally 0.52 ml of triethylamine, and the mixture was stirred under a hydrogen atmosphere for a further 60 minutes. According to LCMS, the detachment of the silyl protecting group remained incomplete. After filtration to remove the solid residues, the filtrate was freed of the solvent under reduced pressure. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (104 mg) with a molecular weight of 404.5 g/mol (C20H24N2O5S); MS (ESI): m/e=405 (M+H+).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][Si:44]([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[Si:44]([O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])([C:57]([CH3:59])([CH3:60])[CH3:58])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(C)[Si](OCCOCCBr)(c1ccccc1)c1ccccc1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Product: CCCCN(CCCC)C(=O)c1cn(CCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 85.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.40 mmol) and (2-(2-bromoethoxy)ethoxy)(tert-butyl)diphenylsilane (165 mg, 0.40 mmol) were converted to the title compound (280 mg, 84%). 1H NMR (CDCl3) δ 8.66 (d, J=2.0 Hz, 1H), 8.16 (dd, J=8.0, 2.0 Hz, 1H), 7.62-7.57 (m, 4H), 7.57 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.42-7.32 (m, 9H), 7.24-7.22 (m, 2H), 5.12 (s, 2H), 3.96 (s, 3H), 3.94-3.85 (m, 2H), 3.69-3.63 (m, 4H), 3.46-3.43 (m, 4H), 3.67 (t, J=5.2 Hz, 2H), 1.65-1.55 (m, 4H), 1.40-1.15 (m, 4H), 1.01 (s, 9H), 1.00-0.85 (m, 6H); MS(ESI+) m/z 819.4 (M+H)+.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@H:52]([N:55](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C:56]([NH2:58])=[NH:57])[CH2:51]2)=[O:49])[CH2:43]1>>[NH:55]([C@H:52]1[CH2:53][CH2:54][N:50]([C:48]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][N:45]2[CH3:47])=[O:49])[CH2:51]1)[C:56]([NH2:58])=[NH:57]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](N(C(=N)N)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=N)N)C4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in preparation 123) and (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3-(4-nitrobenzyloxycarbonylguanidino)pyrrolidin-1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 99) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl.O>O1CCCC1>[CH3:12][O:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-hydroxybenzaldehyde (1.0 g) in tetrahydrofuran (25 mL) was added sodium hydride (374 mg) at 0° C. and the mixture was stirred at 0° C. for 20 minutes. Methoxymethylchloride (0.92 mL) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The reaction mixture was poured into cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:1→5:1) to give the title compound (1.36 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21]Br)=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1.C[NH2:33].C1COCC1>CN(C=O)C>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@@H:9]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:20]=2[CH2:21][NH2:33])=[O:15])[CH2:10][CH2:11][CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CBr)c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)c1cnn(-c2ccc(Cl)cc2)c1CN)c1cccc(C(F)(F)F)c1
Yield: 44 %

Procedure:
A solution of 5-bromomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (50 mg, 0.091 mmol) in DMF (2 mL) is treated with methylamine in THF (2.0 N solution, 49 μL, 0.091 mmol) and the resultant solution is heated in a microwave at 125° C. for 5 min. The crude reaction mixture is concentrated in vacuo and purified by preparative reverse phase HPLC (eluted with 10 to 90% CH3CN/H2O and 0.1% TFA as additive) to afford 5-aminomethyl-1-(4-chloro-phenyl)-1H-pyrazole-4-carboxylic acid [(S)-1-(3-trifluoromethyl-phenyl)-butyl]-amide (20 mg, 44%).
Reaction SMILES: [NH:1]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:16](N(C)C)N(C)C>>[N:4]12[PH:16]34[N:10]([CH2:9][CH2:8][N:7]3[CH2:6][CH2:5]1)[CH2:11][CH2:12][CH2:13][N:1]4[CH2:2][CH2:3]2
Reactant: C1CNCCNCCNCCNC1
Reactant: CN(C)P(N(C)C)N(C)C
Product: C1CN2CCN3CCN4CCN(C1)[PH]234

Procedure:
A mixture of 4.00 g (21.5 mmol) of 1,4,7,10-tetraazacyclotridecane and 3.50 g (21.5 mmol) of hexamethylphosphorous triamide is heated for 2 hr under nitrogen at 125° and then distilled under vacuum to give 3.84 g (83%) of clear, colorless, viscous liquid 1,4,8,11-tetraaza-14-phosphatetracyclo[6.5.1.04,14.011,14 ]tetradecane, bp 92° (0.30 mm).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1.C(N(CC)CC)C>CC#N.O>[Br:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][N:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=2[Cl:2])[CH2:11][CH2:12]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: BrCc1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1cccc(N2CCN(Cc3cccc(Br)c3)CC2)c1Cl
Yield: 55 %

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine hydrochloride (intermediate 41) (294 mg, 1.1 mmol), 1-bromo-3-(bromomethyl)benzene (250 mg, 1 mmol) and anhydrous triethylamine (253 mg, 2.5 mmol) was dissolved in CH3CN and the solution was heated to reflux for 4 h. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=8:1) to give 1-(3-bromobenzyl)-4-(2,3-dichlorophenyl)piperazine (intermediate 53) (220 mg, 74%) as a white solid.
Reaction SMILES: II.[CH3:3][N:4]([CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1S(Cl)(=O)=O)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:37]([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[SH:37][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:5]([N:4]([CH3:17])[CH3:3])=[O:6]
Reactant: O=S([O-])[O-]
Reactant: CN(C)C(=O)c1ccccc1S(=O)(=O)Cl
Agent: II
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc(S)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Iodine (1 g) was added to a stirred solution of 3-[(dimethylamino)carbonylbenzenesulfonyl chloride (2 g) (Borthwick et al, J. Med. Chem 2002, 45(1), 1-18) and triphenylphosphine (8.4 g) in 1,4-dioxane at 0° C. The mixture was stirred for 0.5 h at ambient temperature. The mixture was poured into a sodium sulphite solution (50 ml), extracted into ethyl acetate (2×30 ml) and washed with 2N sodium hydroxide solution (2×40 ml). The alkaline extracts were acidified and re-extracted into dichloromethane (3×50 ml). The extracts were washed with water (100 ml), dried (Na2SO4) and evaporated to give the title compound as a colourless solid (1.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:37])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)O)C1=O

Procedure:
0.28 g of t-butyl α-{6-[1-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl}acetate [prepared as described in Example 7(i) above (the first fraction)] was subjected to de-t-butylation with trifluoracetic acid in the same manner as described in Example 3, giving the title compound as an amorphous solid in a yield of 0.18 g.