Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[OH-].[Na+].[Br:14]Br>C(O)(=O)C.[Zn]>[Br:14][C:6]1[C:2]([CH3:1])=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH:5]=1
Reactant: BrBr
Reactant: CCOC(=O)c1sccc1C
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1scc(Br)c1C
Temperature: 85 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A solution of ethyl 3-methyl-2-thiophenecarboxylate (20.0 g, 0.118 mol) and sodium hydroxide (12.3 g, 0.307 mol) in acetic acid (75 mL) was heated to 60° C. Bromine (46.9 g, 0.294 mol) was added dropwise at such a rate so as to maintain the temperature of the reaction mixture at <85° C. When the addition was complete, the resulting solution was stirred at 85° C. for 6 hours, at which time analysis by gas chromatography/mass spectrometry showed complete conversion to ethyl 4,5-dibromo-3-methyl-2-thophenecarboxylate. The solution was allowed to cool to 50° C. and zinc dust (15.4 g, 0.236 mol) was added in 3 gram portions such that the exotherm was controlled to remain below 85° C. When the addition was completed, the resulting slurry was stirred at 85° C. for one hour. The solution was filtered hot through a small bed of celite. Water (300 mL) was added and the mixture was extracted with heptanes (300 mL). The organic phase was washed with water, then concetrated to dryness to give 26.9 g (89%) as an off white oil which slowly crystallized upon standing at ambient temperature. In a similar fashion, methyl 3-methyl-2-thiophenecarboxylate may be converted methyl-4bromo-3-methyl-2-thiophenecarboxyltate in 97% yield.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=[NH:33])=[CH:30][CH:29]=2)[C:15]2[NH:19][C:18](=[O:20])[N:17]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:16]=2)=[CH:10][C:9]=1[O:37][CH3:38])[CH3:6]>C(O)(=O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH2:34])=[NH:33])=[CH:35][CH:36]=2)[C:15]2[NH:19][C:18](=[O:20])[N:17]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)[N:16]=2)=[CH:10][C:9]=1[O:37][CH3:38])[CH3:6]
Reactant: CCOc1ccc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc1OC
Solvent: CC(=O)O
Product: CCOc1ccc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc1OC
Yield: 26.7 %

Procedure:
A SUMICHIRAL OA-2500 column was used for optical resolution of 75 mg of 4-{[(4-ethoxy-3-methoxyphenyl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzamidine acetate (produced by the same procedure as in Example (18g), using 0.1% acetic acid instead of the 0.1% trifluoroacetic acid in Example (18g)), and the first fraction (20 mg) of the title compound was obtained as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].C([O:9][C:10]1[CH2:14][CH2:13][CH2:12][C:11]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21](=[O:23])[CH3:22])(=O)C.BrBr.[Ca]>CN(C)C(=O)C.C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.O>[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10](=[O:9])[CH2:14][CH2:13][CH:12]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCCCCCC1=C(OC(C)=O)CCC1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCCCCC1=CCCC1=O

Procedure:
To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3 l. of water, and 2.5 l. of chloroform cooled to 5°C. is added simultaneously 1016 g. (4.0 moles) of 1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 56) and a solution of 648 g. (4.05 moles) of bromine in 500 ml. of carbon tetrachloride at a rate to maintain a temperature below 10°C. The mixture is stirred for half an hour after addition of the reagents and the phases are then separated. The organic phase is washed with 2% sodium thiosulfate solution, water, and saturated brine, dried (MgSO4), and evaporated in vacuo to an oil. The oil is immetiately added to a refluxing a slurry of 500 g. (5.0 moles) of calcium carbonaate in 2.5 l of N,N-dimethylacetamide under nitrogen and the mixture is then refluxed for thirty minutes. The mixture is cooled, filtered, and partitioned between water and diethyl. The organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated to yield 757 g. of an oil, b.p. 116°-118°C. (0.25 mm.).
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:13]([C:16]1[CH:17]=[C:18]([CH:21]=O)[NH:19][CH:20]=1)(=[O:15])[CH3:14].C1COCC1>N1CCCCC1.CC(O)C>[C:13]([C:16]1[CH:17]=[C:18](/[CH:21]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[C:3]([I:12])[C:2]([F:1])=[CH:10][CH:9]=3)[NH:19][CH:20]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1c[nH]c(C=O)c1
Reactant: O=C1Cc2c(ccc(F)c2I)N1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Temperature: 25 °C

Procedure:
1,3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.77 g, 2.8 mmol) (see Example 2A, supra) and 4-acetyl-2-formylpyrrole (0.42 g, 3.06 mmol) (Example 90A above) were suspended in 1% piperidine in 2-propanol (12 mL) and THF (5 mL) and heated at 85° C. for 2 h. Yellow precipitate was formed. After cooling to room temperature, product was collected by filtration and washed with aqueous 2-propanol and dried in vacuum oven to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one. (Yield 0.89 g, 80.8%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2cnc(Cn3cc(N)cn3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cnc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.9 min; [M+H]+=393.96.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([C:14](=[O:15])[CH3:13])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Yield: 50.1 %

Procedure:
Following the general procedure of Example 39, Step 2, 6-chloro-2-(chloromethyl) imidazo[1,2-α]pyridine (Example 4. Step 1; 0.294 g), 4-piperazinoacetophenone (Aldrich; 0.366 g), and THF (3 mL) are converted to product, which is chromatographed on silica gel using methanol/dichlormethane (2/98), followed by crystallization from ethyl acetate/dichloromethane, to give 0.270 g of the title compound in two crops; mp 185.5-187° C.; MS m/z 368; IR (mineral oil) 1600, 1661, 1252, 1327, 1197 cm-1 ; 1H NMR (CDCl3) δ2.52, 2.72, 3.40, 3.76, 6.86, 7.13, 7.52, 7.54, 7.86, 8.15.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].[O:21]1C[CH2:24][CH2:23][CH2:22]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(O)CCO.C(P(CCCC)CCCC)CCC>C(OCC)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:24][CH2:23][CH2:22][OH:21])(=[O:10])=[O:11]
Reactant: C1CCOC1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: OCCCO
Solvent: CCOCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of 318 mg (0.951 mmol) of 3-(5-chloro-1,3-dimethyl-pyrazole-4-sulfonyloxy)-5-methylphenol, as prepared in the preceding step, in 5 mL of anhydrous tetrahydrofuran containing 360 mg (1.42 mmol) of 1,1'-(azodicarbonyl)dipiperidine and 150 μL (2.07 mmol) of 1,3-propanediol was added slowly 350 μL (1.41 mmol) of tri-n-butylphosphine. The reaction mixture was stirred for 1 h at ambient temperature, diluted with diethyl ether, and filtered. The filtrate was concentrated and purified by flash chromatography (ethyl acetate/dichloromethane (2:1)) to give 227 mg (64% yield) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3) δ 6.64-6.65 (m, 1H), 6.52-6.54 (m, 1H), 6.46-6.47 (t, 1H), 4.06 (t, 2H, J=6 Hz), 3.83 (t, 2H, J=6 Hz), 3.82 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 2.00 (pentet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C15H19ClN2O5S: 375.1 (M+H), 397.1 (M+Na). Found: 374.9, 397.1.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:35])([CH3:34])[CH2:26][NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.C(Cl)Cl.Cl[CH2:40][S:41](Cl)(=[O:43])=[O:42]>O>[F:35][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][S:41]([CH3:40])(=[O:43])=[O:42])[CH:14]=2)=[CH:24][CH:23]=1)([CH3:34])[CH2:26][NH:27][S:28]([CH:31]([CH3:32])[CH3:33])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A 50 mL flask fitted with a stirrer and thermometer was charged with DBU (67 mg, 1.1 eq), {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine (140 mg, 0.44 mmol, prepared in example 5) and methylene chloride (10 mL) under an atmosphere of nitrogen, and cooled to 0° C. To this stirring solution was added dropwise chloro-methane sulfonyl chloride (69 mg, 1.5 eq). The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H2O and the layers were separated. The organic layer was washed once with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum to yield the crude material (192 mg) as a yellow oil. This crude material was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Methylene Chloride/ethyl acetate 9:1 to yield the title compound (50 mg, 29%) as a white foam. Ion spray mass spectra 427.1 (M*−1).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].Cl.[NH:25]1[CH2:28][CH:27]([C:29]#[N:30])[CH2:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[C:5]([O:22][CH3:23])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:25]3[CH2:28][CH:27]([C:29]#[N:30])[CH2:26]3)=[O:20])=[C:14]([F:21])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: N#CC1CNC1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)O)c(F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To a solution of 3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylic acid (70 mg, 0.2 mmol), azetidine-3-carbonitrile hydrochloride (30 mg, 0.25 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.25 mmol) in N,N-dimethylformamide (0.42 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol). After being stirred at room temperature for 2 h, the mixture was diluted with ethyl acetate, washed with water, brine, dried and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (25 mg, 30% in 3 steps). LCMS calculated for C21H19ClFN2O3 (M+H)+: m/z=401.1. found: 401.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([CH2:21][CH3:22])[CH:3]=1.Br[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(N(CC)C(C)C)(C)C.CN1CCCC1>C(OCC)(=O)C>[CH2:8]([C:6]1[CH:7]=[C:2]([N:1]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=[C:4]([CH2:21][CH3:22])[C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:9]
Reactant: CCc1cc(N)cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Reactant: BrCCOCCBr
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(N2CCOCC2)cc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Temperature: 180 °C
Yield: 91 %

Procedure:
A mixture of N-(4-amino-2,6-diethyl-phenyl)-4-methyl-benzenesulfonamide (70 mg), bis-(2-bromoethyl)ether (33 μL), N,N-diisopropyl-ethylamine (115 μL) and N-methylpyrrolidine (0.3 mL) was heated to 180° C. for 20 minutes in a sealed microwave process vial. The mixture was diluted with ethyl acetate (20 mL), washed with brine (30 mL) and saturated aqueous potassium carbonate (30 mL), and dried over sodium sulfate. The organic phase was concentrated in vacuo to furnish 78 mg (91%) of the title compound. LC-MS (m/z) 389 (MH+); tR=2.77, (UV, ELSD) 57%, 98%. The crude product was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([OH:16])[C:13]([OH:17])=[CH:12][N:11]=2)=[O:9])[CH2:4][CH2:3]1.C(C(CCCC)C([O-])=O)C.[Na+].FC(F)(F)C(O)=O.[NH2:36][C:37]1[S:41][N:40]=[C:39]([C:42](=[N:60][O:61][CH2:62][CH:63]=[CH2:64])[C:43]([NH:45][C@@H:46]2[C:58](=[O:59])[N:48]3[C:49]([C:55]([OH:57])=[O:56])=[C:50]([CH2:53]Cl)[CH2:51][S:52][C@H:47]23)=[O:44])[N:38]=1.C(OCC)(=O)C>CS(C)=O>[NH2:36][C:37]1[S:41][N:40]=[C:39]([C:42](=[N:60][O:61][CH2:62][CH:63]=[CH2:64])[C:43]([NH:45][C@@H:46]2[C:58](=[O:59])[N:48]3[C:49]([C:55]([O-:57])=[O:56])=[C:50]([CH2:53][N+:2]4([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]5[CH:15]=[C:14]([OH:16])[C:13]([OH:17])=[CH:12][N:11]=5)=[O:9])[CH2:4][CH2:3]4)[CH2:51][S:52][C@H:47]23)=[O:44])[N:38]=1
Reactant: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reactant: CN1CCN(C(=O)c2cc(O)c(O)cn2)CC1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Reaction time: 4 h
Yield: 34.2 %

Procedure:
To a suspension of 1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)piperazine (800 mg) in dimethyl sulfoxide (8 ml) was added sodium 2-ethylhexanoate (840 mg). The solution was added dropwise a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate trifluoroacetate (syn isomer) (965 mg) in dimethyl sulfoxide (7 ml) at room temperature. After being stirred for 4 hours, the mixture was poured into ethyl acetate (200 ml) and the resulting precipitates were collected by filtration. The precipitates were dissolved in water and then adjusted to pH 3.0 with aqueous sodium bicarbonate. The resulting solution was subjected to column chromatography on Diaion HP-20 using 15% aqueous isopropyl alcohol as an eluent and the objective fraction was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-allyloxyiminoacetamido]-3-[1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (380 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=O)=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.[CH3:31][C:32]([NH2:36])([CH3:35])[CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:36][C:32]([CH3:35])([CH3:31])[CH2:33][NH:34][C:27]([C:24]1[CH:25]=[CH:26][C:18]2[C:17]3[S:30][C:14]([C:9]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:12](=[O:13])[NH:11][N:10]=4)=[CH:15][C:16]=3[CH2:22][CH2:21][O:20][C:19]=2[CH:23]=1)=[O:29]
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Reactant: CC(C)(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(N)CNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with 2-methylpropane-1,2-diamine, HATU and DIPEA in THF to give 332 as a colorless solid after reverse phase HPLC. MS: (ESI+) 510.0
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:24])=[O:23])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccnc2c(N)cccc12
Solvent: c1ccncc1
Product: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 66 %

Procedure:
In a similar fashion using route 14 general procedure 26, 8-Amino-quinoline-4-carboxylic acid methyl ester 489 (56 mg, 0.27 mmol), benzenesulfonyl chloride (54 mg, 0.30 mmol) and pyridine (5 ml) gave the title compound (61 mg, 64%) after purification by column chromatography with DCM/EtOAc (90:10 as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([OH:37])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(Br)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-tert-butyl 4′-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate (20 mg, 0.03 mmol) in TFA/DCM (1 mL, 30%) was stirred at rt for 2 h. The completion of the reaction was monitored by anal. HPLC. The solvent was removed to obtain the crude which was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z): 581/583 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC1N=C(OC)N=C(OC)[N:30]=1.CN1CCOCC1.[OH-].[NH4+]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[O:23][C:22]([C:24]([NH2:30])=[O:25])=[CH:21][CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(=O)O)o1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(N)=O)o1
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a room temperature suspension of 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoic acid (1.00 g, 2.27 mmol) in THF (8.0 mL) was added 2-chloro-4,6 dimethoxy-1,3,5 triazine (610 mg, 3.47 mmol) and N-methyl morpholine (NMM, 368 mg, 3.62 mmol) sequentially. The resulting solution was matured for 2 hours and then a saturated aqueous solution of ammonium hydroxide (1.5 mL) was added. The resulting suspension was allowed to continue for 1 additional hour. The reaction mixture was diluted with 800 mL of brine and extracted with ethyl acetate (3×600 mL). The organic extracts were separated, Na2SO4 dried, and concentrated in vacuo and the resulting residue was subjected to SiO2 chromatography with ethyl acetate/hexanes/methanol (57:38:5) to provide the title compound (710 mg, 71%). 1H NMR (400 MHz, d7-DMF) δ 8.07 (s, 1H), 7.79 (app q, J=8.6 Hz, 1H), 7.50 (br s, 1H), 7.32 (app dt, J=10.1, 2.2 Hz, 1H), 7.30 (app dd, J=8.0, 3.3 Hz, 1H), 7.20 (app dt, J=8.6, 2.0 Hz, 1H), 6.81 (s, 1H), 6.79 (d, J=3.4 Hz, 1H), 5.47 (s, 2H), 2.14 (s, 3H); LC/MS C-18 column, tr=2.60 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 439 (M+H). ES-HRMS m/z 439.0088 (M+H calcd for C18H14BrF2N2O4 requires 439.0010).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[C:25]([NH2:38])[C:26]3[C:30]([CH:31]=2)=[N:29][N:28](C2CCCCO2)[CH:27]=3)[CH:20]=[CH:21][CH:22]=1>C1COCC1>[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[N:28][NH:29]3)=[C:25]([NH:38][C:13]([CH:10]3[CH2:12][CH2:11]3)=[O:14])[CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccc(-c2cc(N)c3cn(C4CCCCO4)nc3c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2cc(NC(=O)C3CC3)c3cn[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
THF (1 ml), DIPEA (0.142 ml, 0.813 mmol) and cyclopropanecarbonyl chloride (34 mg, 0.325 mmol) were added to 6-(3-methylphenyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg, 0.163 mmol) and the reaction was stirred at RT for 1 h. The solvent was evaporated under a stream of nitrogen and 2 M sodium hydroxide (aq) (3 ml) was added and the reaction stirred for 1 h. DCM (3 ml) was added and the reaction stirred for a further 30 mins. The organic layer was passed through a hydrophobic frit and the aqueous layer extracted with DCM. The combined organic layers were concentrated. The residue was dissolved in MeOH (2 ml) and 4 M HCl in 1,4-dioxane (2 ml) was added. The reaction was stirred for 1 h then the solvent was removed in vacuo. The residue was purified by MDAP (Method A) then freeze dried to give title compound, 17 mg.