Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([C:33]4[O:34][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[C:40]([O:44]C)[CH:39]=5)=[N:36][N:37]=4)[CH:17]=[C:18]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(=O)=O.CC(C)=O>ClCCl>[CH:22]1[C:21]2[N:20]([C:18]3[CH:17]=[C:16]([C:33]4[O:34][C:35]([C:38]5[CH:39]=[C:40]([OH:44])[CH:41]=[CH:42][CH:43]=5)=[N:36][N:37]=4)[CH:15]=[C:14]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:19]=3)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1cccc(-c2nnc(-c3cc(-n4c5ccccc5c5ccccc54)cc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-(3,5-dicarbazol-9-ylphenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (0.95 g, 1.63 mmol) in dichloromethane (20.0 ml) was dropwise added BBr3 (7.0 ml, 1M in dichloromethane) at −78° C. (dry-ice/acetone) under nitrogen. After addition of BBr3 solution, the reaction was taken to room temperature and kept at room temperature for 5.5 h. The reaction mixture was poured into ice-water (70.0 ml). Dichloromethane was evaporated under reduced pressure. The white solid was collected by filtration. After drying under vacuum, product as white solid was obtained in 0.92 g (98.9%) yield. 1H NMR (400 MHz, DMSO-d6, δ): 10.01 (s, br, 1H, OH), 8.46 (d, J=1.6 Hz, 2H), 8.28 (d, J=8.0 Hz, 4H), 8.17 (t, J=1.6 Hz, 111), 7.66 (d, J=8.0 Hz, 4H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (m, 5H), 7.34 (m, 5H), 7.00 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H). MS-EI (m/z): [M]+ calcd for C38H24N4O2, 568.2. found 568.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]>O1CCCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(CO)ccc1Cl
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(C=O)ccc1Cl
Yield: 79.6 %

Procedure:
To a well stirred solution of 2-chloro-5-hydroxymethyl-benzenesulfonamide (31.6 g, 143 mmol) in 300 mL tetrahydrofuran is added 62.0 g (713 mmol) of MnO2. The resulting solution is heated at reflux for 16 h, filtered through Celite then through a 0.4 μM Teflon filter and the filtrate is concentrated in vacuo to remove the tetrahydrofuran. Trituration with hexanes provided 25 g (80%) of the title compound as a grey solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[CH3:23][S:24]([CH2:27][CH2:28][NH2:29])(=[O:26])=[O:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:17])[CH3:18])[C:13]([NH:29][CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:15])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: CS(=O)(=O)CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)NCCS(C)(=O)=O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 39.6 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL), 2-(methylsulfonyl)ethanamine hydrochloride (8.2 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (8 mg, 39.2%). 1H NMR (400 MHz, CD3OD) δ 0.91 (d, J=6.82 Hz, 3 H) 1.05 (d, J=6.32 Hz, 3 H) 2.50 (dq, J=17.94, 6.57 Hz, 1 H) 2.92 (s, 3 H) 3.22-3.28 (m, 1 H) 3.33-3.38 (m, 1 H) 3.61 (dt, J=14.40, 6.57 Hz, 1 H) 3.73 (dt, J=14.40, 6.57 Hz, 1 H) 4.94-5.13 (m, 2 H) 5.19-5.40 (m, 1 H) 7.85 (s, 1 H) 8.17 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C17H21FN4O4S, 398; found, 398.3.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[SH:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[Cl:9][C:8]1[C:7]([Cl:10])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:2][S:12][C:13]1[N:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: Oc1ccnc(S)n1
Product: Oc1ccnc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Yield: 89 %

Procedure:
As per procedure from Example 1, this compound was prepared from 2-(bromomethyl)-1,3,4-trichlorobenzene and 2-sulfanylpyrimidin-4-ol to provide the title compound as a white solid (1.04 g, 89% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.72 (s, 2H), 6.21 (bs, 1H), 7.58 (d, J=8.8 Hz 1H), 7.68 (d, J=8.8 Hz 1H), 8.02 (bs, 1H); M+322.8.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17](O)[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([F:7])[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)c1ccc(C(=O)C(O)c2cccc(Cl)c2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)C(F)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution 6.7 g diethylaminosulfur trifluoride in 20 ml of dry dichloromethane was stirred at -78° C. under nitrogen as a solution of 12 g of 2-(3-chlorophenyl)-2-hydroxy-1-[4-(dimethylamino)phenyl]ethanone in 200 ml of dry dichloromethane was added dropwise. The mixture was warmed to room temperature and stirred for 72 hours. The mixture was poured into 200 ml of ice water and the layers separated. The organic layer was dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography (8:1 hexane-ethyl acetate) and then recrystallized from ether-hexane to give 1.1 g of 2-(3-chlorophenyl)-2-fluoro-1-[4-(dimethylamino)phenyl]ethanone, mp 90°-92° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23](Cl)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1.N1C=CC=CC=1>ClCCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23]([O:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Cl)C[C@@H]1C
Reactant: Oc1cccnc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Oc2cccnc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
A solution of (S)-4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride (0.050 g, 0.13 mmol) in 1,2-dichloroethane (1 mL) was added dropwise to a 50° C. solution of pyridine-3-ol (0.053 g, 0.26 mmol) and pyridine (1 mL) in 1,2-dichloroethane (20 mL). The resulting solution was stirred for 6 h at 50° C. and then concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1-20% methanol-dichloromethane) and then by preparative-HPLC (conditions: Column, SunFire™Prep C18OBD™, 19×150 nm; Mobile phase, A: 0.05% ammonium carbonate, B: acetonitrile; Detector, 220 and 254 nm) to afford (S)-pyridin-3-yl 4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.026 mg, 46%) as a white solid. 1H NMR (300 MHz, CD3OD) 1.17 (d, J=6.60 Hz, 3H), 2.27 (s, 3H), 3.50-3.79 (m, 1H), 4.35-4.45 (m, 1H), 5.02-5.25 (m, 5H), 5.55-5.65 (m, 1H), 7.39-7.49 (m, 2H), 7.51-7.57 (m, 1H), 7.78-7.83 (m, 1H), 7.97 (s, 1H), 8.10-8.19 (m, 2H), 8.47-8.50 (m, 1H), 8.52-8.56 (m, 1H). MS (ESI, pos. ion) m/z 434 [M+H]+.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:9]=1[C:10]([NH:12][CH2:13][C:14]1([C:26]2[C:31](O)=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:16][CH2:15]1)=[O:11]>CN(C=O)C.O>[Cl:7][C:8]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:9]=1[C:10]([NH:12][CH2:13][C:14]1([C:26]2[C:31]([O:4][CH3:1])=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:18][CH2:19]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2O)CC1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2OC)CC1

Procedure:
The [11C]MeI was trapped at 0° C. in a mixture of 2,4-dichloro-N-{[4-(3-hydroxypyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}benzamide (0.25 mg) in DMF (0.2 mL) containing Cs2CO3 (1-2 mg). This mixture was transferred to a vial at 100° C. and heated for five minutes. The reaction was diluted with H2O (0.8 μL) and purified by HPLC (Waters C18 XTerra, 7.8×150 mm, 5 μm, 15 minutes linear gradient 20% MeCN:(95:5:0.1) H2O:MeCN:TFA to 90% MeCN @ 3 mL/min, product elutes at 8.5 minutes). The product fraction was collected in a heated round bottom flask attached to a rotary evaporator, the solvent was removed and the product was transferred to a vial using physiologic saline to give to give 65 mCi of [11C] 2,4-dichloro-N-{[4-(3-methoxypyridin-2-yl)-1-(propylsulfonyl)piperidin-4-yl]methyl}benzamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:28]1[CH:29]=[N:30][NH:31][CH:32]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COc1ccc2c(-c3cn[nH]c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give [6-methoxy-1-(1H-pyrazol-4-yl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 307(MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]O)[CH:2]=[CH2:3].S(Cl)([Cl:15])=O.CN(C=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][Cl:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1cccc(CCl)c1

Procedure:
To a solution of 3-allyloxybenzyl alcohol (7.2 g) in dichloromethane (100 ml) at 0° C. was added thionyl chloride (4.8 ml) in dichloromethane dropwise and a drop of DMF and the mixture stirred at ambient temperature for 1.5 hours, and poured into cold sodium bicarbonate solution. The organic layer was washed with sodium bicarbonate (2×100 ml), dried (magnesium sulphate), filtered and evaporated to give 3-allyloxybenzyl chloride (8.3 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]3[NH:30][C:29](=[O:31])[O:28][C:27]([CH3:33])([CH3:32])[C:26]=3[CH:34]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH:35]O>>[C:12]([C:9]1[CH:8]=[C:7]([S:16]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]3[NH:30][C:29](=[O:31])[O:28][C:27]([CH3:33])([CH3:32])[C:26]=3[CH:34]=2)=[O:35])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc(C(C)(C)C)c1O
Reactant: OO
Product: CC(C)(C)c1cc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc(C(C)(C)C)c1O

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,5-ditert.butyl-4-hydroxy-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:9]4[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:10]=4[CH2:11][CH2:12][C:13]=3[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:22](B(O)O)[CH:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH2:22]([C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:9]4[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:10]=4[CH2:11][CH2:12][C:13]=3[CH:14]=2)[CH:5]=[CH:4][CH:3]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: Cc1cc(C)c2c(c1)-c1nc3cccc(Cl)c3cc1CC2
Reactant: CC(C)CB(O)O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1)-c1nc3cccc(CC(C)C)c3cc1CC2
Temperature: 25 °C
Yield: 92.4 %

Procedure:
8-chloro-2,4-dimethyl-5,6-dihydrobenzo[c]acridine (15.0 g, 51.1 mmol), isobutylboronic acid (7.8 g, 77 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.6 g, 4.08 mmol) potassium phosphate monohydrate (41.2 g, 179 mmol) were mixed in 300 mL of toluene. The system was degassed for 20 minutes. Pd2(dba)3 (0.93 g, 1.02 mmol) was then added and the system was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered through a Celite® plug and eluted with 30% ethyl acetate in toluene. ˜19.5 crude liquid was obtained. The crude product was recrystallized from 5% acetone in hexane to obtain ˜14.9 g pure product (99.6%) which was confirmed by GC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 61.2 %

Procedure:
Beginning with 4.0 gm (26.0 mMol) 6-chloro-1H-indole and 8.0 gm (52.0 mMol) 4-piperidone hydrochloride monohydrate, 3.7 gm (61%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[C:17]([CH3:23])=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[C:17]=2[CH3:23])=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3C)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c3C)c2cc1OC
Yield: 80 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline (93 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (105 mg, 0.3 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea (134 mg, 0.24 mmol, 79%). 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.60 (s, 1H), 7.47-7.32 (m, 5H), 7.25 (t, 1H), 6.96 (d, 1H), 6.37 (s, 1H), 3.99 (s, 6H), 2.36 (s, 3H), 1.95 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:9][C:10]([C:12]1[N:16]2[C@@:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=3)([CH3:29])[C:18](=[O:28])[N:19]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]2=[N:14][CH:13]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.[NH4+].[Cl-].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:9][C:10]([C:12]1[N:16]2[C@@:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:43]4[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)([CH3:29])[C:18](=[O:28])[N:19]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]2=[N:14][CH:13]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(Br)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A solution of (S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid tert-butyl ester (0.20 g, 0.32 mmol), 4-fluorophenyl boronic acid (0.059 g, 0.43 mmol) and K2CO3 (0.15 g, 1.1 mmol) in DME (5 mL) was degassed under N2 for 10 minutes. To this was added PdCl2(dppf) (5 mg) and the mixture heated at 80° C. for 12 h. The resulting black mixture was cooled to room temperature, diluted with saturated NH4Cl and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water, brine, dried with MgSO4 and concentrated. The residue was purified by silica gel chromatography to afford 150 mg of (S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-(4′-fluoro-biphenyl-4-ylmethyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid tert-butyl ester as a white solid, m/z 637.5 [M+]+.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([F:10])[CH2:7][C@H:6]1[C:11]#[N:12])=[O:4].Cl.F[C@@H]1CN[C@H](C(N)=O)C1.[Cl:23]CC(Cl)=O>>[Cl:23][CH2:2][C:3]([N:5]1[CH2:9][C@@H:8]([F:10])[CH2:7][C@H:6]1[C:11]#[N:12])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Agent: Cl
Agent: NC(=O)[C@@H]1C[C@H](F)CN1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl

Procedure:
According to the production process of (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile described in WO 02/38541 pamphlet, (2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride (5.00 g) and chloroacetyl chloride (2.60 mL) were used to obtain (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (4.96 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:12][C:7]1[C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:8]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
6-Bromo-4-fluoro-2-nitroaniline was prepared using an adaptation of the method of Mitchell et al., J. Org. Chem. 44: 4733 (1979). To a solution of 4-fluoro-2-nitroaniline (500 mg, 3.2 mmol) in dry DMF (16 mL) under N2 was added dropwise a solution of N-bromosuccinimide (570 mg, 3.2 mmol) in dry DMF (16 mL). The reaction was allowed to stir 24 h. The solution was then poured into 100 mL H2O and this aqueous phase extracted with 4×25 mL CH2Cl2. The combined organic phases were washed with 3×4 mL H2O and dried (MgSO4). The MgSO4 was vacuum filtered and the solvent rotary evaporated to yield a brown oil which crystallized on standing. 642 mg (85.4%). 1H NMR (CDCl3) δ 6.51 (br s, 2H NH2), 7.58 (dd, JH4-3 -3 Hz, JH4-F =6.5 Hz, H-4), 7.92 (dd, JH3-F =3 Hz, JH3-F =8.7 Hz, H-3).
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[N:5]2[C:18](=[O:31])[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:4]2[C:3]1=[O:32].[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.N1C=CC=CC=1.[C:57](OC(=O)C)(=[O:59])[CH3:58]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:57]([O:32][CH:3]1[C@@H:4]2[CH:19]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[N:5]2[CH:6]([C:7]([O:9][CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:14])([CH3:15])[CH3:16])=[O:8])[CH:2]1[CH3:1])(=[O:59])[CH3:58]
Reactant: CC1C(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCOC(=O)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(C)c1ccncc1
Agent: [BH4-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)OC1C(C)C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@@H]12
Temperature: -10 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
By the procedure of Example 18, pivaloyloxymethyl 2-methyl-1-oxo-6-(2-phenoxyacetamido)carbapenam-3-carboxylate (135 mg., 0.3 mmoles) was reduced with tetrabutylammonium borohydride and the isolation taken to the stage at which a washed, dried and filtered solution of pivaloyloxymethyl 1-hydroxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate in methylene chloride was in hand. This solution was cooled to -10° C. Pyridine (24 mg., 0.3 mmoles), acetic anhydride (31 mg., 0.3 mmoles) and 4-dimethylaminopyridine (4 mg., 0.3 mmoles) were added in sequence. After stirring for 1 hour at -10° C., tlc (4:1 chlorform:ethyl acetate) indicated complete acetylation. The reaction mixture was diluted with toluene and stripped to dryness in vacuo, with toluene chases. Chromatography on silica gel (20:1 methylene chloride:ethyl acetate) gave pivaloyloxymethyl 1-acetoxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate [10 mg.; Rf 0.36 (4:1 chloroform:ethyl acetate); ir (CH2Cl2) 1780, 1750, 1685 cm-1 ].
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]3[CH:34]=[N:35][C:36]([C:37](=[N:39]O)[NH2:38])=[C:32]3[C@@H:31]3[CH2:41][CH2:42][N:30]3[C:29](=[O:43])[C:28]=2[CH:44]=1>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]3[CH:34]=[N:35][C:36]([C:37]4[N:39]=[C:4]([CH2:3][N:2]([CH3:7])[CH3:1])[O:5][N:38]=4)=[C:32]3[C@@H:31]3[CH2:41][CH2:42][N:30]3[C:29](=[O:43])[C:28]=2[CH:44]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reactant: CN(C)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CN(C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Temperature: 90 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
1.75 g (17 mmol) of N,N-dimethylglycine were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 3.08 g (15 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 70° for 30'. Then, 4.02 g (15 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° C. overnight. By evaporation of the solution, chromatography of the residue on 240 g of silica gel while eluting with methylene chloride/methanol 19/1 and crystallization from ethyl acetate there were obtained 1.35 g (24%) of (S)-7-fluoro-12,12a-dihydro-1-[5-(dimethylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 187°-190°, which was converted into the hydrochloride of m.p. 150°-155°.